{"gene":"NUPR1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2021,"finding":"NUPR1 drives ferroptosis resistance by transcriptionally upregulating LCN2, which reduces iron accumulation and subsequent oxidative damage. LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, and re-expression of LCN2 restores ferroptosis resistance in NUPR1-deficient cells.","method":"NanoString gene expression, shRNA knockdown (NUPR1 and LCN2), pancreas-specific conditional knockout mice, enforced LCN2 re-expression, ferroptosis induction assays with erastin, mouse models of pancreatitis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic approaches (shRNA, conditional KO, re-expression), validated in vitro and in vivo, replicated with pharmacological inhibitor ZZW-115","pmids":["33510144"],"is_preprint":false},{"year":2017,"finding":"NUPR1 maintains autolysosomal efflux by transcriptionally inducing the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE-associated protein VAMP8. NUPR1 depletion impairs autophagic flux and induces massive cytoplasmic vacuolization and premature senescence.","method":"NUPR1 depletion (RNAi), transcriptional induction assays, co-immunoprecipitation of SNAP25/VAMP8 complex, autophagy flux assays, senescence assays in vitro and tumor suppression in vivo","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional validation with multiple orthogonal methods (RNAi, Co-IP, in vitro and in vivo assays), mechanistic pathway clearly defined","pmids":["29130426"],"is_preprint":false},{"year":2008,"finding":"NUPR1 forms a complex with p53 and p300 and binds the p21 promoter to transcriptionally upregulate p21 expression, conferring resistance to doxorubicin and Taxol.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP) on p21 promoter, reporter assays, doxorubicin/Taxol resistance assays","journal":"Current cancer drug targets","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP in single lab with functional chemoresistance validation","pmids":["18690848"],"is_preprint":false},{"year":2009,"finding":"NUPR1 (p8) binds MSL1, a histone acetyltransferase (HAT)-associated protein, and negatively regulates MSL1-dependent DNA repair activity following gamma-irradiation. MSL1 binds the DNA-damage-associated protein 53BP1 to facilitate DNA repair, and p8 interaction inhibits this repair activity. NUPR1 expression is transiently induced then downregulated after irradiation, presumably to allow MSL1-associated DNA repair to proceed.","method":"Protein-protein interaction assays, cell-based DNA repair assays, gamma-irradiation, 53BP1 knockdown experiments","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis and binding established in single lab with multiple assays","pmids":["19650074"],"is_preprint":false},{"year":2013,"finding":"Nupr1 and MSL1 form a complex in the nucleus in response to DNA damage, essential for cell survival in response to cisplatin. MSL1 binds Nupr1 with an affinity of ~2.8 µM (entropically driven), and MSL1 binds chemically damaged DNA with ~1.2 µM affinity. The binding region of Nupr1 in its complexes is always disordered ('fuzzy').","method":"Spectroscopic and biophysical methods (fluorescence, ITC, NMR), Co-IP in nucleus, cisplatin survival assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with quantitative affinities (ITC, fluorescence), NMR mapping, confirmed in cellulo with functional validation (cisplatin survival)","pmids":["24205110"],"is_preprint":false},{"year":2017,"finding":"NUPR1 binds the C-terminal region of Polycomb RING1B (C-RING1B) with affinity in the low micromolar range (~10 µM). The binding region of NUPR1 was mapped by NMR to a hydrophobic patch at the 30s region (around Ala33). Mutation of Ala33 to Gln reduces binding. This interaction is inhibited by trifluoperazine and occurs in cellulo (by protein ligation assays).","method":"NMR, computational docking, isothermal titration calorimetry, site-directed mutagenesis (Ala33Gln, Thr68Gln), protein ligation assays in cellulo","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR mapping + mutagenesis + ITC + in cellulo validation, multiple orthogonal methods in single rigorous study","pmids":["28720707"],"is_preprint":false},{"year":2019,"finding":"ZZW-115 (a TFP-derived compound) binds NUPR1 around residue Thr68 in the nuclear localization signal (NLS) region, competing with importins and thereby completely inhibiting nuclear translocation of NUPR1. This mechanism underlies its anticancer (necroptosis-inducing) activity.","method":"Biophysical binding assays (ITC, fluorescence), computer modeling, nuclear translocation assays, cell death mechanistic assays (necroptosis markers), xenograft tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding, mechanistic nuclear translocation assay, in vivo validation, multiple orthogonal methods","pmids":["30920390"],"is_preprint":false},{"year":2020,"finding":"NUPR1 interacts with several hundreds of proteins including importins, DNA repair proteins, and key SUMO pathway factors. ZZW-115 competes with importins for binding to the NLS region of NUPR1, inhibiting nuclear translocation. NUPR1 inhibition reduces SUMOylation of DNA damage response (DDR) proteins; recombinant NUPR1 directly stimulates the SUMOylation machinery in a cell-free system.","method":"Interactome mass spectrometry, nuclear translocation assays, SUMOylation assays in cells and cell-free system with recombinant NUPR1, genotoxic agent sensitization assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1 / Strong — cell-free reconstitution of SUMOylation activity, interactome by MS, nuclear translocation assay, multiple orthogonal validations","pmids":["32780723"],"is_preprint":false},{"year":2012,"finding":"NUPR1 confers chemoresistance in p53-deficient breast cancer cells by promoting Akt-mediated phosphorylation and subsequent cytoplasmic re-localization of p21 and activation of anti-apoptotic Bcl-xL, defining a NUPR1-PI3K/Akt-phospho-p21 axis.","method":"NUPR1 knockdown/overexpression, p21 localization by immunofluorescence/fractionation, Akt inhibitor experiments, chemoresistance assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation of p21 with pathway inhibitor validation, single lab with multiple orthogonal methods","pmids":["22858377"],"is_preprint":false},{"year":2012,"finding":"Nupr1 protects pancreatic cancer cells from metabolic stress-induced autophagy-associated cell death through regulation of Aurora kinase A (AURKA). Nupr1 knockdown enhances DNA damage, alters gene expression related to DNA repair and cell cycle, and AURKA expression is partially regulated by Nupr1.","method":"Affymetrix transcriptome analysis, RNAi silencing, AURKA overexpression, DNA damage markers (Western blot and immunofluorescence), autophagy markers, human TMA analysis","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome + functional RNAi + overexpression experiments, single lab","pmids":["22899799"],"is_preprint":false},{"year":2018,"finding":"Inactivation of NUPR1 induces mitochondrial failure (loss of membrane potential, increased ROS, decreased OXPHOS/ATP production), relocalization of mitochondria near the ER, and downregulation of ER stress response genes, leading to programmed necrosis (reversed by Necrostatin-1 but not Z-VAD-FMK). In vivo, NUPR1 protects acinar cells from necrosis during ER stress in acute pancreatitis.","method":"NUPR1 knockdown, mitochondrial membrane potential assays, OXPHOS/ATP measurement, ROS measurement, mitochondria/ER co-localization imaging, transcriptomic analysis, thapsigargin/brefeldin A/tunicamycin treatment, acute pancreatitis mouse model, Necrostatin-1 and Z-VAD-FMK rescue experiments","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (metabolic, imaging, transcriptomic, pharmacological rescue), validated in vivo; single lab but comprehensive","pmids":["30451898"],"is_preprint":false},{"year":2021,"finding":"NUPR1 binds PARP1 in the nucleus and inhibits PARP1 activity in vitro. Inhibition of NUPR1 (genetically or by ZZW-115) induces hyperPARylation, mitochondrial catastrophe (decreased membrane potential, superoxide production, increased ROS, cytosolic Ca2+ elevation), and cell death through non-canonical Parthanatos (without AIF translocation from mitochondria). This is rescued by PARP inhibitor olaparib or NAD+ precursor NMN.","method":"Proteomic interactome, Co-IP (NUPR1-PARP1), in vitro PARP1 activity assay with recombinant NUPR1 and NUPR1 mutants, PARylation assays, mitochondrial function assays, olaparib rescue, NAD+/NADH ratio measurement","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of PARP inhibition with recombinant protein, mutagenesis, proteomic interactome, multiple functional rescue experiments","pmids":["35869257"],"is_preprint":false},{"year":2021,"finding":"NUPR1 inhibitor ZZW-115 induces ROS accumulation and ferroptotic cell death in a mitochondria-dependent manner. ZZW-115 causes loss of GSH/GPX antioxidant activity, hydroperoxided lipid accumulation, and mitochondrial morphological changes. TFAM (key regulator of mitochondrial biogenesis) is downregulated by ZZW-115, and forced TFAM expression rescues mitochondrial alterations, ROS production, and cell death.","method":"ROS assays, lipid peroxidation assays, ferroptosis inhibitor (ferrostatin-1) rescue, GSH/GPX activity assays, mitochondrial morphology imaging, TFAM overexpression rescue, xenograft models","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (lipid peroxidation, ROS, mitochondrial function, TFAM rescue), validated in vivo","pmids":["34599149"],"is_preprint":false},{"year":2012,"finding":"NUPR1 transcriptionally regulates DNMT1 expression to modulate genome-wide DNA methylation levels, thereby acting as a gene modifier of Kras(G12D)-induced senescence. Nupr1 inactivation in mice leads to increased β-galactosidase-positive cells and upregulation of senescence marker genes via the FoxO3a-Skp2-p27(Kip1)-pRb-E2F pathway.","method":"Nupr1 genetic knockout in KrasG12D mice, β-galactosidase senescence assays, gene expression analysis, DNMT1 expression assays, 5-aza-2'-deoxycytidine treatment, RNAi in human pancreatic cancer cells","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with pathway validation and in vitro RNAi confirmation, single lab","pmids":["24902898"],"is_preprint":false},{"year":2015,"finding":"Nupr1 acts as a gene modifier of Kras(G12D)-induced senescence by regulating Dnmt1 expression and genome-wide DNA methylation levels, preventing senescence in lung and pancreatic cells to allow transformation.","method":"Nupr1-/- mouse models with KrasG12D in pancreas and lung, DNA methylation analysis, DNMT1 expression, senescence assays, 5-aza-2'-deoxycytidine treatment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with multiple tissue validation, single lab","pmids":["26617245"],"is_preprint":false},{"year":2012,"finding":"NUPR1 transcriptionally regulates human NUPR1 expression is activated by TGFβ at the transcriptional level through SMAD proteins binding to a functional TGFβ-response element located in the 5'-UTR of the NUPR1 gene.","method":"Promoter-reporter assays, SMAD ChIP, 5'-UTR deletion/mutation analysis, TGFβ treatment experiments","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with promoter mutation and SMAD binding confirmed, single lab","pmids":["22738338"],"is_preprint":false},{"year":2016,"finding":"NUPR1 overexpression decreases levels of the histone acetyltransferase MOF (KAT8) and H4K16 acetylation. Cr(VI)-induced reduction of H4K16 acetylation is substantially compromised by NUPR1 knockdown, indicating NUPR1 mediates the Cr(VI)-induced loss of this cancer-associated epigenetic mark.","method":"NUPR1 overexpression and knockdown, H4K16ac Western blot, MOF expression assays, Cr(VI) treatment, anchorage-independent growth assays, cell transformation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with epigenetic readout, functional cancer transformation assay, single lab","pmids":["27285315"],"is_preprint":false},{"year":2020,"finding":"Phosphorylation of Thr68 in the NLS region of NUPR1 induces a conformational switch from random-coil to a turn-like structure, which hampers binding to importin α3 (Impα3). Positive charges at Lys65 and Lys69 are critical for importin binding. The NLS region of NUPR1 binds Impα3 with low micromolar affinity (1.7–27 µM depending on mutant).","method":"2D-1H-NMR (NOE analysis), fluorescence spectroscopy, ITC, molecular docking, phospho-mimetic and alanine mutants of NLS peptides","journal":"Biomolecules","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR conformational analysis, quantitative ITC binding affinities, mutagenesis of phosphorylation site, multiple orthogonal biophysical methods","pmids":["32933064"],"is_preprint":false},{"year":2021,"finding":"NUPR1 interacts with eIF2α and its phosphorylated form (p-eIF2α) in the nucleus. Loss of NUPR1 results in maintained eIF2α phosphorylation and slower post-stress protein synthesis recovery, implicating NUPR1 in resolution of the PERK branch of the unfolded protein response.","method":"Co-immunoprecipitation, proximity ligation assays (PLA), bioinformatic analysis of interactome, click chemistry for nascent protein synthesis, NUPR1 knockout mouse pancreatic acinar cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and PLA confirmation of interaction, functional nascent protein synthesis assay, single lab","pmids":["33403797"],"is_preprint":false},{"year":2022,"finding":"NUPR1 interacts with aryl hydrocarbon receptor (AhR) and promotes its degradation via the autophagy-lysosome pathway and decreased nuclear translocation, thereby suppressing CYP transcription. This reduces ROS production and confers radioresistance in hepatocellular carcinoma.","method":"Co-immunoprecipitation, RNA sequencing, AhR nuclear translocation assays, pharmacological AhR activation, lysosome inhibition assays, xenograft models, NUPR1 knockdown","journal":"BMC medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional AhR degradation and rescue validation in vitro and in vivo, single lab","pmids":["36258210"],"is_preprint":false},{"year":2022,"finding":"NUPR1 promotes proliferation and metastasis in oral squamous cell carcinoma by directly increasing TFE3 transcription factor activity, thereby maintaining autophagic flux and lysosomal function.","method":"Tandem mass tag quantitative proteomics, NUPR1 stable knockdown, TFE3 activity assays, autophagy flux assays, in vitro and in vivo tumor growth and metastasis models","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics + functional knockdown + in vivo validation, single lab","pmids":["35462576"],"is_preprint":false},{"year":2024,"finding":"NUPR1 induces droplet formation via liquid-liquid phase separation (LLPS) and is required for stress granule (SG) formation in pancreatic cancer cells. KrasG12D mutation induces NUPR1 overexpression and promotes SG development; enforced NUPR1 expression alone induces SG formation independently of KrasG12D. Inhibition of NUPR1 by ZZW-115 impedes SG formation and selectively kills KrasG12D-expressing cells via caspase 3 activation.","method":"LLPS assays, stress granule imaging, ZZW-115 pharmacological inhibition, NUPR1 genetic overexpression, KrasG12D mouse model (KC mice), caspase 3 activation, LDH release, PanIN analysis in vivo","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — LLPS biochemical assay + stress granule imaging + in vivo KC mouse model with multiple molecular readouts, mechanistically defined","pmids":["38360999"],"is_preprint":false},{"year":2023,"finding":"NUPR1 binds PADI4 (peptidyl-arginine deiminase 4) mainly in the nucleus, with a dissociation constant of ~18 µM. The binding region of NUPR1 involves the hydrophobic patch around Ala33 (mapped by NMR and confirmed by Ala33 mutagenesis).","method":"NMR (binding region mapping), ITC (affinity measurement), site-directed mutagenesis (Ala33), proximity ligation assays (PLA) in cellulo, immunofluorescence, molecular modelling","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR + mutagenesis + quantitative ITC + in cellulo PLA, single lab but multiple orthogonal methods","pmids":["36858171"],"is_preprint":false},{"year":2020,"finding":"NUPR1 binds PKP1 (Plakophilin 1) at the armadillo-repeat domain with ~10 µM affinity; the binding region of NUPR1 is the 30s region (around Ala33). This interaction occurs in the nucleus as confirmed by proximity ligation assays.","method":"Fluorescence spectroscopy, NMR, molecular docking, isothermal titration calorimetry, protein ligation assays in cellulo, immunofluorescence","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR mapping + quantitative binding + in cellulo confirmation, single lab","pmids":["33385445"],"is_preprint":false},{"year":2021,"finding":"Nupr1 mediates TGF-β-induced myofibroblast activation (α-SMA expression, collagen synthesis) by initiating the Smad3 signaling pathway in kidney fibroblasts and epithelial cells undergoing EMT. Nupr1 deficiency attenuates UUO-induced renal fibrosis in mice, and TFP (NUPR1 inhibitor) alleviates fibrosis.","method":"Nupr1-/- mice with UUO model, TGF-β stimulation of primary fibroblasts and epithelial cells, Smad3 phosphorylation assays, α-SMA/collagen expression, TFP pharmacological inhibition","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model + in vitro TGF-β signaling pathway validation + pharmacological rescue, single lab","pmids":["33617091"],"is_preprint":false},{"year":2016,"finding":"NUPR1 silencing in HCC cells reduced expression of RELB, IER3, and RUNX2 genes and downregulated NF-κB and ERK signaling nodes, demonstrating a NUPR1/RELB/IER3/RUNX2 regulatory pathway in hepatocarcinogenesis.","method":"NUPR1 stable knockdown, gene expression profiling (microarray), RELB/IER3/RUNX2 knockdown experiments, cell growth/migration/invasion assays, sorafenib sensitivity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic pathway mapping plus individual gene knockdown validation, single lab","pmids":["27336713"],"is_preprint":false},{"year":2013,"finding":"NUPR1 promotes cell cycle progression in pancreatic beta cells by suppressing Ccna2 and Tcf19 promoter activities. Nupr1 deletion increases beta cell mass through enhanced islet cell proliferation.","method":"Nupr1-/- mice, BrdU incorporation for proliferation, luciferase promoter reporter assays for Ccna2 and Tcf19, gene arrays, morphometric analysis of islets","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays plus in vivo KO phenotypic validation, single lab","pmids":["23900510"],"is_preprint":false},{"year":2015,"finding":"NUPR1 knockdown in liver cancer cells suppressed invasion in a Ca2+-signaling-dependent manner. NUPR1 promoter binding assay identified granulin as a key downstream effector of NUPR1 in a mitochondrial defect-related pathway.","method":"NUPR1 knockdown, invasion assays, Ca2+ signaling inhibition, NUPR1-centric network analysis, promoter binding assay for granulin","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional invasion assay with Ca2+ signaling mechanistic link and promoter binding confirmation, single lab","pmids":["26173068"],"is_preprint":false},{"year":2022,"finding":"NUPR1 interacts with SREBP1 and upregulates lipogenic gene expression (FASN), resulting in lipid accumulation that promotes hepatocellular carcinoma progression. Pharmacological or genetic blockade of the NUPR1-SREBP1/FASN pathway reduces tumor growth in vitro and in vivo.","method":"Co-immunoprecipitation (endogenous NUPR1-SREBP1), FASN and lipid accumulation assays, NUPR1 knockdown/overexpression, xenograft tumor models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional lipogenesis validation, single lab","pmids":["36307402"],"is_preprint":false},{"year":2022,"finding":"NUPR1 promotes proliferation and metastasis in breast cancer by activating TFE3 transcription, thereby inducing autophagy. NUPR1 knockdown inhibits malignancy formation and metastasis in vivo.","method":"NUPR1 knockdown, TFE3 transcription assays, autophagy marker analysis, breast cancer in vitro and xenograft in vivo models","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth (transcription activation assay without direct binding confirmation)","pmids":["35660538"],"is_preprint":false},{"year":2016,"finding":"Nupr1 in the METH-exposure context acts upstream of the CHOP-P53-PUMA/Beclin1 pathway to induce mitochondrial apoptosis in endothelial cells. CHOP upregulation by Nupr1 leads to Beclin1 induction, which forms a ternary complex with Bcl-2 to reduce free Bcl-2 and promote cytochrome c release and caspase activation.","method":"shRNA/siRNA silencing of Nupr1, CHOP, P53, PUMA, Beclin1; Western blot for pathway markers; apoptosis assays; cytochrome c translocation assay; in vitro and in vivo (rat) models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic pathway defined by systematic sequential knockdown of each node, single lab","pmids":["27031958"],"is_preprint":false},{"year":2023,"finding":"SETD4 methyltransferase represses NUPR1 transcription by catalyzing H3K27 trimethylation (H3K27me3) at the NUPR1 locus, thereby inactivating the Akt pathway and suppressing prostate cancer development.","method":"SETD4 knockdown/overexpression, H3K27me3 ChIP, NUPR1 expression assays, Akt pathway analysis, prostate cancer cell proliferation and cell cycle assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for H3K27me3 at NUPR1 locus with functional pathway rescue, single lab","pmids":["37879429"],"is_preprint":false},{"year":2022,"finding":"Loss of Nupr1 in hematopoietic stem cells (HSCs) activates quiescent HSCs and confers engraftment advantage. Nupr1 inhibits p53 expression in HSCs; rescue of p53 offsets the engraftment advantage of Nupr1-/- HSCs, placing Nupr1 upstream of p53 in HSC quiescence regulation.","method":"Nupr1 conditional knockout, serial transplantation assays, p53 rescue experiments, in vitro expansion assays, quiescence analysis by flow cytometry","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by p53 rescue experiment, in vivo transplantation, single lab","pmids":["33299232"],"is_preprint":false},{"year":2023,"finding":"Nupr1 regulates HtrA1 (a serine protease) expression in osteoblasts/osteocytes, thereby suppressing SMAD1 signaling and osteoblastogenesis. Nupr1 deficiency reduces HtrA1 expression and enhances SMAD1 signaling; Nupr1 overexpression enhances HtrA1 expression.","method":"Nupr1-KO mice, differential gene expression analysis in osteocytes, in vitro primary osteoblast cultures with Nupr1 overexpression/deficiency, SMAD1 phosphorylation assays, senescence marker analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vitro confirmed in in vivo KO model, single lab","pmids":["36715607"],"is_preprint":false},{"year":2025,"finding":"Tumor-derived lactate upregulates NUPR1 expression in macrophages via histone lactylation, and NUPR1 in turn inhibits ERK and JNK signaling pathways, promoting M2 macrophage polarization and increased expression of PD-L1 and SIRPA.","method":"scRNA-seq, functional in vitro and in vivo assays, histone lactylation analysis, ERK/JNK signaling pathway assays, NUPR1 knockdown in macrophages, PD-1 blockade combination experiments","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — histone lactylation mechanism linked to NUPR1 expression, signaling pathway validation, single lab with multiple orthogonal methods","pmids":["40305758"],"is_preprint":false},{"year":2025,"finding":"NR3C1 (glucocorticoid receptor) directly regulates NUPR1 transcription in response to psychological stress, which in turn increases SNAI2 (Slug) expression to drive EMT and ovarian tumor metastasis.","method":"Chronic restraint stress mouse model, NR3C1 transcriptional regulation assay at NUPR1 promoter, SNAI2 expression assays, EMT marker analysis, NR3C1-NUPR1 correlation in patient data","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo stress model with transcriptional epistasis (NR3C1→NUPR1→SNAI2), single lab","pmids":["40654365"],"is_preprint":false},{"year":2025,"finding":"FTO (m6A demethylase) stabilizes NUPR1 mRNA by targeting the +451 m6A site, thereby preventing YTHDF2-mediated degradation of NUPR1 mRNA, leading to increased NUPR1 protein and downstream LCN2/FTH1-mediated iron homeostasis and chemoresistance in colorectal cancer.","method":"CRISPR/Cas9 FTO knockout cells and mice, m6A site mapping, YTHDF2 interaction assays, mRNA stability assays, LCN2/FTH1 expression analysis, chemotherapy sensitivity assays","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A site-specific mechanism with CRISPR KO validation and YTHDF2 reader mechanistic link, single lab","pmids":["40334546"],"is_preprint":false},{"year":2023,"finding":"WTAP promotes NUPR1 expression via m6A modification in an eIF3A-mediated manner (m6A-EIF3A), which in turn upregulates LCN2 and suppresses ferroptosis in triple-negative breast cancer.","method":"m6A dot blot assay, NUPR1 mRNA stability assay, RIP assay (eIF3a-NUPR1 interaction), NUPR1 silencing, LCN2 knockdown, ferroptosis markers (GSH/GSSG, Fe2+)","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and m6A assay linking WTAP to NUPR1 mRNA stability, functional downstream LCN2/ferroptosis validation, single lab","pmids":["37477758"],"is_preprint":false},{"year":2021,"finding":"NUPR1 promotes FTH1 transcription in HCC cells (via the circPIAS1/miR-455-3p/NUPR1/FTH1 axis), enhancing iron storage and conferring ferroptosis resistance. CircPIAS1 sequesters miR-455-3p to upregulate NUPR1.","method":"RNA immunoprecipitation, luciferase reporter assays, ChIP (NUPR1 on FTH1 promoter), FISH, NUPR1 inhibitor ZZW-115, ferroptosis assays, xenograft models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming NUPR1 binding to FTH1 promoter with functional ferroptosis validation, single lab","pmids":["38802795"],"is_preprint":false},{"year":2021,"finding":"NUPR1 promotes PPAR-α signaling via the UPR, protecting liver from lipotoxic injury. NUPR1 loss-of-function in mice fed high-fat diet results in impaired UPR activation and reduced PPAR-α signaling, leading to increased hepatic steatosis.","method":"Nupr1-/- mice on high-fat diet, UPR pathway analysis, PPAR-α signaling assays, patient liver biopsy analysis, immunohistochemistry, mRNA analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with pathway mechanistic validation, single lab","pmids":["33566371"],"is_preprint":false},{"year":2024,"finding":"NUPR1 mediates METH-induced pulmonary arterial smooth muscle cell (PASMC) phenotypic conversion from contractile to synthetic by activating STIM1 expression, which opens store-operated calcium entry (SOCE) channels, promoting Ca2+ influx and pulmonary artery remodeling.","method":"NUPR1 expression analysis in human/mouse lung specimens, PASMC NUPR1 knockdown/overexpression, STIM1 expression assays, Ca2+ influx (SOCE) measurement, pulmonary artery remodeling histology, right ventricular systolic pressure measurement","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STIM1-SOCE mechanistic link established by gain/loss-of-function with Ca2+ measurement, single lab","pmids":["38347241"],"is_preprint":false},{"year":2019,"finding":"Amphipathic helical peptides bind to NUPR1 around Ala33 and C-terminus residues (low micromolar Kd ~3 µM), inhibiting NUPR1-RING1B interaction in cellulo. The Thr68Gln mutant of NUPR1 does not interact with these peptides.","method":"Fluorescence, circular dichroism, NMR, ITC, docking/MD simulations, proximity ligation assays (in cellulo for NUPR1-RING1B interaction inhibition), site-directed mutagenesis (Thr68Gln)","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR + ITC + mutagenesis + in cellulo PLA, single lab with multiple orthogonal biophysical methods","pmids":["29530795"],"is_preprint":false},{"year":2008,"finding":"Loss of NUPR1 (p8) in mice results in delayed LHB (luteinizing hormone beta subunit) expression during gonadotroph development, ovarian maturation delay (absence of corpora lutea at 8 weeks), and age-related testicular germ cell loss resembling Sertoli-cell-only syndrome, demonstrating a role for NUPR1 in temporal regulation of LHB and gonadal function.","method":"Nupr1-/- mouse model, RT-qPCR for LHB/FSHB/GATA2/CGA/TSH expression at embryonic time points, gonadal histology, corpora lutea assessment","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with developmental phenotype characterization at multiple time points, single lab","pmids":["18495683"],"is_preprint":false},{"year":2019,"finding":"AP-1 (via JUN binding sites) transcriptionally regulates NUPR1 in response to nickel exposure. Knockdown of JUN or FOS suppresses NUPR1 induction by Ni. Deletion of the upstream JUN binding site in the NUPR1 promoter reduces promoter activity.","method":"Luciferase reporter assay with NUPR1 promoter, JUN binding site deletion (site-directed mutagenesis), JUN/FOS knockdown experiments, NUPR1 promoter cloning","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis and epistasis by transcription factor knockdown, single lab","pmids":["33649793"],"is_preprint":false}],"current_model":"NUPR1 is a small, intrinsically disordered nuclear protein that functions as a stress-inducible transcriptional coregulator and chromatin-associated factor; it drives ferroptosis resistance by transcriptionally upregulating LCN2 (reducing iron accumulation) and FTH1 (enhancing iron storage), binds and inhibits PARP1 to protect against hyperPARylation-dependent cell death, promotes autolysosomal efflux by inducing SNAP25/VAMP8 SNARE complex formation, undergoes importin α3-mediated nuclear translocation regulated by phosphorylation of Thr68 in its NLS, and engages multiple chromatin partners (including p53/p300, MSL1/53BP1, RING1B, PADI4, PKP1, SREBP1, eIF2α, and AhR) via a conserved hydrophobic hot spot around Ala33 and Thr68 to modulate DNA repair, UPR resolution, lipogenesis, EMT, and stress granule formation via liquid-liquid phase separation."},"narrative":{"mechanistic_narrative":"NUPR1 is a small, intrinsically disordered, stress-inducible nuclear factor that acts as a transcriptional coregulator and chromatin-associated hub coordinating cell survival under genotoxic, metabolic, and ER stress [PMID:33510144, PMID:30451898]. A central output of NUPR1 is protection against regulated cell death: it transcriptionally upregulates the iron-handling genes LCN2 (limiting iron accumulation and oxidative damage) and FTH1 (enhancing iron storage) to confer ferroptosis resistance [PMID:33510144, PMID:38802795], and it binds and inhibits PARP1 in the nucleus to prevent hyperPARylation-driven, non-canonical Parthanatos and mitochondrial catastrophe [PMID:35869257]. NUPR1 also sustains autophagic and lysosomal homeostasis, transcriptionally inducing the SNARE protein SNAP25 that complexes with VAMP8 to maintain autolysosomal efflux [PMID:29130426] and activating TFE3 to preserve autophagic flux [PMID:35462576]. Mechanistically, NUPR1 engages partners through a conserved disordered ('fuzzy') hydrophobic hot spot around Ala33, which mediates low-micromolar binding to chromatin and repair-associated factors including MSL1, RING1B, PADI4, and PKP1 [PMID:24205110, PMID:28720707, PMID:36858171, PMID:33385445], while phosphorylation of Thr68 within its nuclear localization signal triggers a conformational switch that disrupts importin α3 binding and gates its nuclear translocation [PMID:32933064, PMID:30920390]. In the nucleus NUPR1 stimulates SUMOylation of DNA damage response proteins [PMID:32780723], cooperates with p53/p300 to drive p21 transcription [PMID:18690848], and regulates DNMT1-dependent DNA methylation to modulate oncogene-induced senescence [PMID:24902898, PMID:26617245]. Its disordered nature also enables liquid-liquid phase separation required for stress granule formation in KrasG12D-driven pancreatic cancer [PMID:38360999]. Through these activities NUPR1 broadly supports tumor cell survival, lipogenesis via SREBP1 [PMID:36307402], and EMT, and it is the pharmacological target of the inhibitor ZZW-115, which blocks its nuclear import and triggers death of cancer cells [PMID:30920390, PMID:35869257].","teleology":[{"year":2008,"claim":"Established NUPR1 as a developmental transcriptional regulator in vivo and as a chromatin-associated partner of p53/p300, framing it as a stress-responsive transcriptional coregulator rather than a passive marker.","evidence":"Nupr1-/- mouse gonadal development phenotyping; Co-IP, p21-promoter ChIP and chemoresistance assays in cancer cells","pmids":["18495683","18690848"],"confidence":"Medium","gaps":["Direct DNA-binding versus adaptor role on the p21 promoter not resolved","Structural basis of the p53/p300 complex undefined"]},{"year":2009,"claim":"Identified MSL1 as a NUPR1 partner and placed NUPR1 as a negative regulator of MSL1/53BP1-dependent DNA repair, linking it to the genotoxic stress response.","evidence":"Protein interaction assays, cell-based DNA repair assays after gamma-irradiation, 53BP1 knockdown","pmids":["19650074"],"confidence":"Medium","gaps":["Binding interface not mapped at this stage","Mechanism of repair inhibition unresolved"]},{"year":2012,"claim":"Connected NUPR1 to metabolic and DNA-methylation control of cell fate, showing it protects against metabolic-stress death via AURKA and chemoresistance via PI3K/Akt-phospho-p21, and is itself a TGFβ/SMAD transcriptional target.","evidence":"Transcriptome profiling, RNAi/overexpression, subcellular fractionation of p21, Akt-inhibitor experiments, SMAD ChIP and 5'-UTR reporter assays","pmids":["22899799","22858377","22738338"],"confidence":"Medium","gaps":["Direct versus indirect regulation of AURKA unclear","How NUPR1 couples to Akt mechanistically not defined"]},{"year":2013,"claim":"Provided the first quantitative biophysical view of NUPR1, showing it binds MSL1 and damaged DNA through a disordered 'fuzzy' interface, defining its mode of action as an intrinsically disordered interaction hub.","evidence":"ITC, fluorescence, NMR with in-nucleus Co-IP and cisplatin survival assays; promoter reporter assays for Ccna2/Tcf19 in beta cells","pmids":["24205110","23900510"],"confidence":"High","gaps":["Structure of the bound state not solved (remains disordered)","Generality of the fuzzy mode across partners not yet shown at this point"]},{"year":2015,"claim":"Extended NUPR1's role to oncogene-induced senescence and tumor invasion, showing DNMT1/DNA-methylation control of Kras-driven senescence and Ca2+-dependent regulation of invasion via granulin.","evidence":"Nupr1-/- KrasG12D mouse models, methylation analysis, 5-aza treatment; invasion assays with Ca2+ signaling inhibition and granulin promoter binding","pmids":["26617245","24902898","26173068"],"confidence":"Medium","gaps":["Direct DNMT1 promoter occupancy not established","Mechanism linking NUPR1 to Ca2+ signaling undefined"]},{"year":2017,"claim":"Mapped the NUPR1 interaction hot spot to the Ala33 hydrophobic patch (RING1B binding) and defined a transcriptional autophagy mechanism (SNAP25/VAMP8), unifying its structural mode with a concrete cell-biological output.","evidence":"NMR mapping, ITC, Ala33Gln mutagenesis, in cellulo ligation assays for RING1B; RNAi, Co-IP of SNAP25/VAMP8 and autophagy flux assays","pmids":["28720707","29130426"],"confidence":"High","gaps":["Whether the same hot spot mediates all partner interactions not yet generalized","Transcriptional versus non-transcriptional contribution to autolysosomal efflux not fully separated"]},{"year":2018,"claim":"Demonstrated that NUPR1 loss causes mitochondrial failure and ER-stress-dependent programmed necrosis, establishing NUPR1 as a guardian of mitochondrial integrity during ER stress.","evidence":"Knockdown with mitochondrial membrane potential/OXPHOS/ROS assays, mitochondria-ER imaging, ER-stress inducers, acute pancreatitis model, Nec-1/Z-VAD rescue","pmids":["30451898"],"confidence":"High","gaps":["Molecular link between NUPR1 and mitochondrial maintenance not identified","Transcriptional targets driving ER-stress resolution incomplete"]},{"year":2019,"claim":"Identified ZZW-115 as a NUPR1 inhibitor that binds the Thr68/NLS region and blocks importin-mediated nuclear import, providing a druggable mechanism and a tool to dissect nuclear functions.","evidence":"ITC/fluorescence binding, modeling, nuclear translocation and necroptosis assays, xenografts; helical-peptide inhibitors of NUPR1-RING1B with Thr68Gln mutants","pmids":["30920390","29530795"],"confidence":"High","gaps":["Off-target effects of ZZW-115 not fully excluded","Which downstream functions are import-dependent not delineated"]},{"year":2020,"claim":"Resolved the import-gating mechanism at residue level — Thr68 phosphorylation drives a coil-to-turn switch impairing importin α3 binding — and revealed NUPR1 directly stimulates SUMOylation of DDR proteins, defining a biochemical nuclear activity.","evidence":"NMR conformational analysis, ITC of NLS-Impα3, phospho-mimetic mutants; interactome MS, cell-free SUMOylation reconstitution with recombinant NUPR1; PKP1 binding by NMR/ITC/PLA","pmids":["32933064","32780723","33385445"],"confidence":"High","gaps":["Kinase responsible for Thr68 phosphorylation not identified","Mechanism by which NUPR1 stimulates the SUMO machinery unresolved"]},{"year":2021,"claim":"Consolidated NUPR1 as a master suppressor of regulated cell death, showing it inhibits PARP1 to block Parthanatos and transcriptionally controls LCN2/FTH1 iron handling to confer ferroptosis resistance.","evidence":"Proteomic interactome, NUPR1-PARP1 Co-IP and in vitro PARP1 activity assays with mutants, olaparib/NMN rescue; NanoString/shRNA/conditional KO and LCN2 re-expression; FTH1 promoter ChIP; TFAM-rescue ferroptosis assays","pmids":["35869257","33510144","38802795","34599149"],"confidence":"High","gaps":["Stoichiometry/site of PARP1 inhibition not structurally defined","How NUPR1 selects between ferroptosis, Parthanatos and necrosis outputs unclear"]},{"year":2022,"claim":"Broadened NUPR1's regulatory reach to lipogenesis, autophagy and UPR resolution, and to additional chromatin partners, positioning it as an integrator of metabolic and proteostatic stress.","evidence":"SREBP1 Co-IP and FASN/lipid assays; TFE3 activity and autophagy assays; AhR Co-IP and autophagic degradation; eIF2α Co-IP/PLA and nascent-synthesis assays; PPAR-α/UPR analysis in KO mice","pmids":["36307402","35462576","36258210","33403797","33566371"],"confidence":"Medium","gaps":["Direct versus indirect engagement of each metabolic partner varies in rigor","Whether these interactions share the Ala33 hot spot not tested for all partners"]},{"year":2023,"claim":"Generalized the Ala33 hydrophobic-patch binding mode to PADI4 and detailed transcriptional/epigenetic control of NUPR1 itself, including SETD4-mediated H3K27me3 repression and m6A-dependent stabilization.","evidence":"NMR/ITC/PLA for PADI4 with Ala33 mutagenesis; SETD4 ChIP for H3K27me3 at the NUPR1 locus; WTAP/eIF3A m6A and mRNA-stability assays","pmids":["36858171","37879429","37477758"],"confidence":"Medium","gaps":["Functional consequence of NUPR1-PADI4 binding not established","Interplay between epigenetic and post-transcriptional control of NUPR1 levels unresolved"]},{"year":2024,"claim":"Showed NUPR1 undergoes liquid-liquid phase separation required for stress granule formation in KrasG12D pancreatic cancer, providing a biophysical basis for its disordered-protein stress functions.","evidence":"In vitro LLPS assays, stress granule imaging, ZZW-115 inhibition, NUPR1 overexpression, KC mouse model with caspase-3 readouts","pmids":["38360999"],"confidence":"High","gaps":["Partner RNAs/proteins co-condensing with NUPR1 not identified","Link between LLPS and the transcriptional/chromatin functions not resolved"]},{"year":2025,"claim":"Embedded NUPR1 in the tumor microenvironment and stress-hormone signaling, showing lactate/histone-lactylation induces it in macrophages to promote M2 polarization and that glucocorticoid-receptor signaling drives NUPR1-dependent EMT.","evidence":"scRNA-seq, histone-lactylation analysis and ERK/JNK assays in macrophages; NR3C1 promoter regulation and SNAI2/EMT in stress mouse models; FTO/YTHDF2 m6A stabilization of NUPR1 mRNA","pmids":["40305758","40654365","40334546"],"confidence":"Medium","gaps":["Cell-intrinsic versus microenvironmental contributions not separated","Mechanism by which NUPR1 suppresses ERK/JNK undefined"]},{"year":null,"claim":"How NUPR1's disordered structure, Thr68-gated nuclear import, phase separation, and partner-selection at the Ala33 hot spot are integrated to choose among its many context-specific outputs (ferroptosis, Parthanatos, autophagy, lipogenesis, EMT) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NUPR1 in any partner complex (interface remains 'fuzzy')","Upstream kinase and signaling that control Thr68 phosphorylation unknown","Determinants of partner/output selection from a single hydrophobic hot spot undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,26,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,4,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,3,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,22,23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5,11,17,18,22,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,21]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,11,10,30]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,20,19]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,18,39]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,26,38]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,4,7]}],"complexes":[],"partners":["PARP1","MSL1","RING1B","PADI4","PKP1","SREBP1","EIF2S1","AHR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60356","full_name":"Nuclear protein 1","aliases":["Candidate of metastasis 1","Protein p8"],"length_aa":82,"mass_kda":8.9,"function":"Transcription regulator that converts stress signals into a program of gene expression that empowers cells with resistance to the stress induced by a change in their microenvironment. Thereby participates in the regulation of many processes namely cell-cycle, apoptosis, autophagy and DNA repair responses (PubMed:11056169, PubMed:11940591, PubMed:16300740, PubMed:16478804, PubMed:18690848, PubMed:19650074, PubMed:19723804, PubMed:20181828, PubMed:22565310, PubMed:22858377, PubMed:30451898). Controls cell cycle progression and protects cells from genotoxic stress induced by doxorubicin through the complex formation with TP53 and EP300 that binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Protects pancreatic cancer cells from stress-induced cell death by binding the RELB promoter and activating its transcription, leading to IER3 transactivation (PubMed:22565310). Negatively regulates apoptosis through interaction with PTMA (PubMed:16478804). Inhibits autophagy-induced apoptosis in cardiac cells through FOXO3 interaction, inducing cytoplasmic translocation of FOXO3 thereby preventing the FOXO3 association with the pro-autophagic BNIP3 promoter (PubMed:20181828). Inhibits cell growth and facilitates programmed cell death by apoptosis after adriamycin-induced DNA damage through transactivation of TP53 (By similarity). Regulates methamphetamine-induced apoptosis and autophagy through DDIT3-mediated endoplasmic reticulum stress pathway (By similarity). Participates in DNA repair following gamma-irradiation by facilitating DNA access of the transcription machinery through interaction with MSL1 leading to inhibition of histone H4' Lys-16' acetylation (H4K16ac) (PubMed:19650074). Coactivator of PAX2 transcription factor activity, both by recruiting EP300 to increase PAX2 transcription factor activity and by binding PAXIP1 to suppress PAXIP1-induced inhibition on PAX2 (PubMed:11940591). Positively regulates cell cycle progression through interaction with COPS5 inducing cytoplasmic translocation of CDKN1B leading to the CDKN1B degradation (PubMed:16300740). Coordinates, through its interaction with EP300, the association of MYOD1, EP300 and DDX5 to the MYOG promoter, leading to inhibition of cell-cycle progression and myogenic differentiation promotion (PubMed:19723804). Negatively regulates beta cell proliferation via inhibition of cell-cycle regulatory genes expression through the suppression of their promoter activities (By similarity). Also required for LHB expression and ovarian maturation (By similarity). Exacerbates CNS inflammation and demyelination upon cuprizone treatment (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/O60356/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUPR1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NUPR1","total_profiled":1310},"omim":[{"mim_id":"614812","title":"NUCLEAR PROTEIN, TRANSCRIPTIONAL REGULATOR, 1; NUPR1","url":"https://www.omim.org/entry/614812"},{"mim_id":"614801","title":"MSL COMPLEX SUBUNIT 1; MSL1","url":"https://www.omim.org/entry/614801"},{"mim_id":"613099","title":"MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 5; CMM5","url":"https://www.omim.org/entry/613099"},{"mim_id":"613098","title":"INCREASED ANALGESIA FROM KAPPA-OPIOID RECEPTOR AGONIST, FEMALE-SPECIFIC","url":"https://www.omim.org/entry/613098"},{"mim_id":"300951","title":"RING FINGER PROTEIN 113A; RNF113A","url":"https://www.omim.org/entry/300951"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"pancreas","ntpm":1078.9}],"url":"https://www.proteinatlas.org/search/NUPR1"},"hgnc":{"alias_symbol":["COM1","p8"],"prev_symbol":[]},"alphafold":{"accession":"O60356","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60356","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60356-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60356-F1-predicted_aligned_error_v6.png","plddt_mean":70.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUPR1","jax_strain_url":"https://www.jax.org/strain/search?query=NUPR1"},"sequence":{"accession":"O60356","fasta_url":"https://rest.uniprot.org/uniprotkb/O60356.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60356/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60356"}},"corpus_meta":[{"pmid":"33510144","id":"PMC_33510144","title":"NUPR1 is a critical repressor of ferroptosis.","date":"2021","source":"Nature 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LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, and re-expression of LCN2 restores ferroptosis resistance in NUPR1-deficient cells.\",\n      \"method\": \"NanoString gene expression, shRNA knockdown (NUPR1 and LCN2), pancreas-specific conditional knockout mice, enforced LCN2 re-expression, ferroptosis induction assays with erastin, mouse models of pancreatitis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic approaches (shRNA, conditional KO, re-expression), validated in vitro and in vivo, replicated with pharmacological inhibitor ZZW-115\",\n      \"pmids\": [\"33510144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NUPR1 maintains autolysosomal efflux by transcriptionally inducing the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE-associated protein VAMP8. NUPR1 depletion impairs autophagic flux and induces massive cytoplasmic vacuolization and premature senescence.\",\n      \"method\": \"NUPR1 depletion (RNAi), transcriptional induction assays, co-immunoprecipitation of SNAP25/VAMP8 complex, autophagy flux assays, senescence assays in vitro and tumor suppression in vivo\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional validation with multiple orthogonal methods (RNAi, Co-IP, in vitro and in vivo assays), mechanistic pathway clearly defined\",\n      \"pmids\": [\"29130426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NUPR1 forms a complex with p53 and p300 and binds the p21 promoter to transcriptionally upregulate p21 expression, conferring resistance to doxorubicin and Taxol.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP) on p21 promoter, reporter assays, doxorubicin/Taxol resistance assays\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP in single lab with functional chemoresistance validation\",\n      \"pmids\": [\"18690848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NUPR1 (p8) binds MSL1, a histone acetyltransferase (HAT)-associated protein, and negatively regulates MSL1-dependent DNA repair activity following gamma-irradiation. MSL1 binds the DNA-damage-associated protein 53BP1 to facilitate DNA repair, and p8 interaction inhibits this repair activity. NUPR1 expression is transiently induced then downregulated after irradiation, presumably to allow MSL1-associated DNA repair to proceed.\",\n      \"method\": \"Protein-protein interaction assays, cell-based DNA repair assays, gamma-irradiation, 53BP1 knockdown experiments\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis and binding established in single lab with multiple assays\",\n      \"pmids\": [\"19650074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nupr1 and MSL1 form a complex in the nucleus in response to DNA damage, essential for cell survival in response to cisplatin. MSL1 binds Nupr1 with an affinity of ~2.8 µM (entropically driven), and MSL1 binds chemically damaged DNA with ~1.2 µM affinity. The binding region of Nupr1 in its complexes is always disordered ('fuzzy').\",\n      \"method\": \"Spectroscopic and biophysical methods (fluorescence, ITC, NMR), Co-IP in nucleus, cisplatin survival assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with quantitative affinities (ITC, fluorescence), NMR mapping, confirmed in cellulo with functional validation (cisplatin survival)\",\n      \"pmids\": [\"24205110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NUPR1 binds the C-terminal region of Polycomb RING1B (C-RING1B) with affinity in the low micromolar range (~10 µM). The binding region of NUPR1 was mapped by NMR to a hydrophobic patch at the 30s region (around Ala33). Mutation of Ala33 to Gln reduces binding. This interaction is inhibited by trifluoperazine and occurs in cellulo (by protein ligation assays).\",\n      \"method\": \"NMR, computational docking, isothermal titration calorimetry, site-directed mutagenesis (Ala33Gln, Thr68Gln), protein ligation assays in cellulo\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR mapping + mutagenesis + ITC + in cellulo validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"28720707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZZW-115 (a TFP-derived compound) binds NUPR1 around residue Thr68 in the nuclear localization signal (NLS) region, competing with importins and thereby completely inhibiting nuclear translocation of NUPR1. This mechanism underlies its anticancer (necroptosis-inducing) activity.\",\n      \"method\": \"Biophysical binding assays (ITC, fluorescence), computer modeling, nuclear translocation assays, cell death mechanistic assays (necroptosis markers), xenograft tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding, mechanistic nuclear translocation assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"30920390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUPR1 interacts with several hundreds of proteins including importins, DNA repair proteins, and key SUMO pathway factors. ZZW-115 competes with importins for binding to the NLS region of NUPR1, inhibiting nuclear translocation. NUPR1 inhibition reduces SUMOylation of DNA damage response (DDR) proteins; recombinant NUPR1 directly stimulates the SUMOylation machinery in a cell-free system.\",\n      \"method\": \"Interactome mass spectrometry, nuclear translocation assays, SUMOylation assays in cells and cell-free system with recombinant NUPR1, genotoxic agent sensitization assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cell-free reconstitution of SUMOylation activity, interactome by MS, nuclear translocation assay, multiple orthogonal validations\",\n      \"pmids\": [\"32780723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NUPR1 confers chemoresistance in p53-deficient breast cancer cells by promoting Akt-mediated phosphorylation and subsequent cytoplasmic re-localization of p21 and activation of anti-apoptotic Bcl-xL, defining a NUPR1-PI3K/Akt-phospho-p21 axis.\",\n      \"method\": \"NUPR1 knockdown/overexpression, p21 localization by immunofluorescence/fractionation, Akt inhibitor experiments, chemoresistance assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation of p21 with pathway inhibitor validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22858377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nupr1 protects pancreatic cancer cells from metabolic stress-induced autophagy-associated cell death through regulation of Aurora kinase A (AURKA). Nupr1 knockdown enhances DNA damage, alters gene expression related to DNA repair and cell cycle, and AURKA expression is partially regulated by Nupr1.\",\n      \"method\": \"Affymetrix transcriptome analysis, RNAi silencing, AURKA overexpression, DNA damage markers (Western blot and immunofluorescence), autophagy markers, human TMA analysis\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome + functional RNAi + overexpression experiments, single lab\",\n      \"pmids\": [\"22899799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Inactivation of NUPR1 induces mitochondrial failure (loss of membrane potential, increased ROS, decreased OXPHOS/ATP production), relocalization of mitochondria near the ER, and downregulation of ER stress response genes, leading to programmed necrosis (reversed by Necrostatin-1 but not Z-VAD-FMK). In vivo, NUPR1 protects acinar cells from necrosis during ER stress in acute pancreatitis.\",\n      \"method\": \"NUPR1 knockdown, mitochondrial membrane potential assays, OXPHOS/ATP measurement, ROS measurement, mitochondria/ER co-localization imaging, transcriptomic analysis, thapsigargin/brefeldin A/tunicamycin treatment, acute pancreatitis mouse model, Necrostatin-1 and Z-VAD-FMK rescue experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (metabolic, imaging, transcriptomic, pharmacological rescue), validated in vivo; single lab but comprehensive\",\n      \"pmids\": [\"30451898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUPR1 binds PARP1 in the nucleus and inhibits PARP1 activity in vitro. Inhibition of NUPR1 (genetically or by ZZW-115) induces hyperPARylation, mitochondrial catastrophe (decreased membrane potential, superoxide production, increased ROS, cytosolic Ca2+ elevation), and cell death through non-canonical Parthanatos (without AIF translocation from mitochondria). This is rescued by PARP inhibitor olaparib or NAD+ precursor NMN.\",\n      \"method\": \"Proteomic interactome, Co-IP (NUPR1-PARP1), in vitro PARP1 activity assay with recombinant NUPR1 and NUPR1 mutants, PARylation assays, mitochondrial function assays, olaparib rescue, NAD+/NADH ratio measurement\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of PARP inhibition with recombinant protein, mutagenesis, proteomic interactome, multiple functional rescue experiments\",\n      \"pmids\": [\"35869257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUPR1 inhibitor ZZW-115 induces ROS accumulation and ferroptotic cell death in a mitochondria-dependent manner. ZZW-115 causes loss of GSH/GPX antioxidant activity, hydroperoxided lipid accumulation, and mitochondrial morphological changes. TFAM (key regulator of mitochondrial biogenesis) is downregulated by ZZW-115, and forced TFAM expression rescues mitochondrial alterations, ROS production, and cell death.\",\n      \"method\": \"ROS assays, lipid peroxidation assays, ferroptosis inhibitor (ferrostatin-1) rescue, GSH/GPX activity assays, mitochondrial morphology imaging, TFAM overexpression rescue, xenograft models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (lipid peroxidation, ROS, mitochondrial function, TFAM rescue), validated in vivo\",\n      \"pmids\": [\"34599149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NUPR1 transcriptionally regulates DNMT1 expression to modulate genome-wide DNA methylation levels, thereby acting as a gene modifier of Kras(G12D)-induced senescence. Nupr1 inactivation in mice leads to increased β-galactosidase-positive cells and upregulation of senescence marker genes via the FoxO3a-Skp2-p27(Kip1)-pRb-E2F pathway.\",\n      \"method\": \"Nupr1 genetic knockout in KrasG12D mice, β-galactosidase senescence assays, gene expression analysis, DNMT1 expression assays, 5-aza-2'-deoxycytidine treatment, RNAi in human pancreatic cancer cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with pathway validation and in vitro RNAi confirmation, single lab\",\n      \"pmids\": [\"24902898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nupr1 acts as a gene modifier of Kras(G12D)-induced senescence by regulating Dnmt1 expression and genome-wide DNA methylation levels, preventing senescence in lung and pancreatic cells to allow transformation.\",\n      \"method\": \"Nupr1-/- mouse models with KrasG12D in pancreas and lung, DNA methylation analysis, DNMT1 expression, senescence assays, 5-aza-2'-deoxycytidine treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with multiple tissue validation, single lab\",\n      \"pmids\": [\"26617245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NUPR1 transcriptionally regulates human NUPR1 expression is activated by TGFβ at the transcriptional level through SMAD proteins binding to a functional TGFβ-response element located in the 5'-UTR of the NUPR1 gene.\",\n      \"method\": \"Promoter-reporter assays, SMAD ChIP, 5'-UTR deletion/mutation analysis, TGFβ treatment experiments\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with promoter mutation and SMAD binding confirmed, single lab\",\n      \"pmids\": [\"22738338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NUPR1 overexpression decreases levels of the histone acetyltransferase MOF (KAT8) and H4K16 acetylation. Cr(VI)-induced reduction of H4K16 acetylation is substantially compromised by NUPR1 knockdown, indicating NUPR1 mediates the Cr(VI)-induced loss of this cancer-associated epigenetic mark.\",\n      \"method\": \"NUPR1 overexpression and knockdown, H4K16ac Western blot, MOF expression assays, Cr(VI) treatment, anchorage-independent growth assays, cell transformation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with epigenetic readout, functional cancer transformation assay, single lab\",\n      \"pmids\": [\"27285315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Phosphorylation of Thr68 in the NLS region of NUPR1 induces a conformational switch from random-coil to a turn-like structure, which hampers binding to importin α3 (Impα3). Positive charges at Lys65 and Lys69 are critical for importin binding. The NLS region of NUPR1 binds Impα3 with low micromolar affinity (1.7–27 µM depending on mutant).\",\n      \"method\": \"2D-1H-NMR (NOE analysis), fluorescence spectroscopy, ITC, molecular docking, phospho-mimetic and alanine mutants of NLS peptides\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR conformational analysis, quantitative ITC binding affinities, mutagenesis of phosphorylation site, multiple orthogonal biophysical methods\",\n      \"pmids\": [\"32933064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUPR1 interacts with eIF2α and its phosphorylated form (p-eIF2α) in the nucleus. Loss of NUPR1 results in maintained eIF2α phosphorylation and slower post-stress protein synthesis recovery, implicating NUPR1 in resolution of the PERK branch of the unfolded protein response.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assays (PLA), bioinformatic analysis of interactome, click chemistry for nascent protein synthesis, NUPR1 knockout mouse pancreatic acinar cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and PLA confirmation of interaction, functional nascent protein synthesis assay, single lab\",\n      \"pmids\": [\"33403797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUPR1 interacts with aryl hydrocarbon receptor (AhR) and promotes its degradation via the autophagy-lysosome pathway and decreased nuclear translocation, thereby suppressing CYP transcription. This reduces ROS production and confers radioresistance in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, RNA sequencing, AhR nuclear translocation assays, pharmacological AhR activation, lysosome inhibition assays, xenograft models, NUPR1 knockdown\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional AhR degradation and rescue validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"36258210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUPR1 promotes proliferation and metastasis in oral squamous cell carcinoma by directly increasing TFE3 transcription factor activity, thereby maintaining autophagic flux and lysosomal function.\",\n      \"method\": \"Tandem mass tag quantitative proteomics, NUPR1 stable knockdown, TFE3 activity assays, autophagy flux assays, in vitro and in vivo tumor growth and metastasis models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics + functional knockdown + in vivo validation, single lab\",\n      \"pmids\": [\"35462576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUPR1 induces droplet formation via liquid-liquid phase separation (LLPS) and is required for stress granule (SG) formation in pancreatic cancer cells. KrasG12D mutation induces NUPR1 overexpression and promotes SG development; enforced NUPR1 expression alone induces SG formation independently of KrasG12D. Inhibition of NUPR1 by ZZW-115 impedes SG formation and selectively kills KrasG12D-expressing cells via caspase 3 activation.\",\n      \"method\": \"LLPS assays, stress granule imaging, ZZW-115 pharmacological inhibition, NUPR1 genetic overexpression, KrasG12D mouse model (KC mice), caspase 3 activation, LDH release, PanIN analysis in vivo\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — LLPS biochemical assay + stress granule imaging + in vivo KC mouse model with multiple molecular readouts, mechanistically defined\",\n      \"pmids\": [\"38360999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUPR1 binds PADI4 (peptidyl-arginine deiminase 4) mainly in the nucleus, with a dissociation constant of ~18 µM. The binding region of NUPR1 involves the hydrophobic patch around Ala33 (mapped by NMR and confirmed by Ala33 mutagenesis).\",\n      \"method\": \"NMR (binding region mapping), ITC (affinity measurement), site-directed mutagenesis (Ala33), proximity ligation assays (PLA) in cellulo, immunofluorescence, molecular modelling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR + mutagenesis + quantitative ITC + in cellulo PLA, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36858171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUPR1 binds PKP1 (Plakophilin 1) at the armadillo-repeat domain with ~10 µM affinity; the binding region of NUPR1 is the 30s region (around Ala33). This interaction occurs in the nucleus as confirmed by proximity ligation assays.\",\n      \"method\": \"Fluorescence spectroscopy, NMR, molecular docking, isothermal titration calorimetry, protein ligation assays in cellulo, immunofluorescence\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR mapping + quantitative binding + in cellulo confirmation, single lab\",\n      \"pmids\": [\"33385445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nupr1 mediates TGF-β-induced myofibroblast activation (α-SMA expression, collagen synthesis) by initiating the Smad3 signaling pathway in kidney fibroblasts and epithelial cells undergoing EMT. Nupr1 deficiency attenuates UUO-induced renal fibrosis in mice, and TFP (NUPR1 inhibitor) alleviates fibrosis.\",\n      \"method\": \"Nupr1-/- mice with UUO model, TGF-β stimulation of primary fibroblasts and epithelial cells, Smad3 phosphorylation assays, α-SMA/collagen expression, TFP pharmacological inhibition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model + in vitro TGF-β signaling pathway validation + pharmacological rescue, single lab\",\n      \"pmids\": [\"33617091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NUPR1 silencing in HCC cells reduced expression of RELB, IER3, and RUNX2 genes and downregulated NF-κB and ERK signaling nodes, demonstrating a NUPR1/RELB/IER3/RUNX2 regulatory pathway in hepatocarcinogenesis.\",\n      \"method\": \"NUPR1 stable knockdown, gene expression profiling (microarray), RELB/IER3/RUNX2 knockdown experiments, cell growth/migration/invasion assays, sorafenib sensitivity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic pathway mapping plus individual gene knockdown validation, single lab\",\n      \"pmids\": [\"27336713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NUPR1 promotes cell cycle progression in pancreatic beta cells by suppressing Ccna2 and Tcf19 promoter activities. Nupr1 deletion increases beta cell mass through enhanced islet cell proliferation.\",\n      \"method\": \"Nupr1-/- mice, BrdU incorporation for proliferation, luciferase promoter reporter assays for Ccna2 and Tcf19, gene arrays, morphometric analysis of islets\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays plus in vivo KO phenotypic validation, single lab\",\n      \"pmids\": [\"23900510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NUPR1 knockdown in liver cancer cells suppressed invasion in a Ca2+-signaling-dependent manner. NUPR1 promoter binding assay identified granulin as a key downstream effector of NUPR1 in a mitochondrial defect-related pathway.\",\n      \"method\": \"NUPR1 knockdown, invasion assays, Ca2+ signaling inhibition, NUPR1-centric network analysis, promoter binding assay for granulin\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional invasion assay with Ca2+ signaling mechanistic link and promoter binding confirmation, single lab\",\n      \"pmids\": [\"26173068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUPR1 interacts with SREBP1 and upregulates lipogenic gene expression (FASN), resulting in lipid accumulation that promotes hepatocellular carcinoma progression. Pharmacological or genetic blockade of the NUPR1-SREBP1/FASN pathway reduces tumor growth in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (endogenous NUPR1-SREBP1), FASN and lipid accumulation assays, NUPR1 knockdown/overexpression, xenograft tumor models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional lipogenesis validation, single lab\",\n      \"pmids\": [\"36307402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUPR1 promotes proliferation and metastasis in breast cancer by activating TFE3 transcription, thereby inducing autophagy. NUPR1 knockdown inhibits malignancy formation and metastasis in vivo.\",\n      \"method\": \"NUPR1 knockdown, TFE3 transcription assays, autophagy marker analysis, breast cancer in vitro and xenograft in vivo models\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth (transcription activation assay without direct binding confirmation)\",\n      \"pmids\": [\"35660538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nupr1 in the METH-exposure context acts upstream of the CHOP-P53-PUMA/Beclin1 pathway to induce mitochondrial apoptosis in endothelial cells. CHOP upregulation by Nupr1 leads to Beclin1 induction, which forms a ternary complex with Bcl-2 to reduce free Bcl-2 and promote cytochrome c release and caspase activation.\",\n      \"method\": \"shRNA/siRNA silencing of Nupr1, CHOP, P53, PUMA, Beclin1; Western blot for pathway markers; apoptosis assays; cytochrome c translocation assay; in vitro and in vivo (rat) models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic pathway defined by systematic sequential knockdown of each node, single lab\",\n      \"pmids\": [\"27031958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SETD4 methyltransferase represses NUPR1 transcription by catalyzing H3K27 trimethylation (H3K27me3) at the NUPR1 locus, thereby inactivating the Akt pathway and suppressing prostate cancer development.\",\n      \"method\": \"SETD4 knockdown/overexpression, H3K27me3 ChIP, NUPR1 expression assays, Akt pathway analysis, prostate cancer cell proliferation and cell cycle assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for H3K27me3 at NUPR1 locus with functional pathway rescue, single lab\",\n      \"pmids\": [\"37879429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of Nupr1 in hematopoietic stem cells (HSCs) activates quiescent HSCs and confers engraftment advantage. Nupr1 inhibits p53 expression in HSCs; rescue of p53 offsets the engraftment advantage of Nupr1-/- HSCs, placing Nupr1 upstream of p53 in HSC quiescence regulation.\",\n      \"method\": \"Nupr1 conditional knockout, serial transplantation assays, p53 rescue experiments, in vitro expansion assays, quiescence analysis by flow cytometry\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by p53 rescue experiment, in vivo transplantation, single lab\",\n      \"pmids\": [\"33299232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nupr1 regulates HtrA1 (a serine protease) expression in osteoblasts/osteocytes, thereby suppressing SMAD1 signaling and osteoblastogenesis. Nupr1 deficiency reduces HtrA1 expression and enhances SMAD1 signaling; Nupr1 overexpression enhances HtrA1 expression.\",\n      \"method\": \"Nupr1-KO mice, differential gene expression analysis in osteocytes, in vitro primary osteoblast cultures with Nupr1 overexpression/deficiency, SMAD1 phosphorylation assays, senescence marker analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vitro confirmed in in vivo KO model, single lab\",\n      \"pmids\": [\"36715607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tumor-derived lactate upregulates NUPR1 expression in macrophages via histone lactylation, and NUPR1 in turn inhibits ERK and JNK signaling pathways, promoting M2 macrophage polarization and increased expression of PD-L1 and SIRPA.\",\n      \"method\": \"scRNA-seq, functional in vitro and in vivo assays, histone lactylation analysis, ERK/JNK signaling pathway assays, NUPR1 knockdown in macrophages, PD-1 blockade combination experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — histone lactylation mechanism linked to NUPR1 expression, signaling pathway validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40305758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NR3C1 (glucocorticoid receptor) directly regulates NUPR1 transcription in response to psychological stress, which in turn increases SNAI2 (Slug) expression to drive EMT and ovarian tumor metastasis.\",\n      \"method\": \"Chronic restraint stress mouse model, NR3C1 transcriptional regulation assay at NUPR1 promoter, SNAI2 expression assays, EMT marker analysis, NR3C1-NUPR1 correlation in patient data\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo stress model with transcriptional epistasis (NR3C1→NUPR1→SNAI2), single lab\",\n      \"pmids\": [\"40654365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FTO (m6A demethylase) stabilizes NUPR1 mRNA by targeting the +451 m6A site, thereby preventing YTHDF2-mediated degradation of NUPR1 mRNA, leading to increased NUPR1 protein and downstream LCN2/FTH1-mediated iron homeostasis and chemoresistance in colorectal cancer.\",\n      \"method\": \"CRISPR/Cas9 FTO knockout cells and mice, m6A site mapping, YTHDF2 interaction assays, mRNA stability assays, LCN2/FTH1 expression analysis, chemotherapy sensitivity assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A site-specific mechanism with CRISPR KO validation and YTHDF2 reader mechanistic link, single lab\",\n      \"pmids\": [\"40334546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WTAP promotes NUPR1 expression via m6A modification in an eIF3A-mediated manner (m6A-EIF3A), which in turn upregulates LCN2 and suppresses ferroptosis in triple-negative breast cancer.\",\n      \"method\": \"m6A dot blot assay, NUPR1 mRNA stability assay, RIP assay (eIF3a-NUPR1 interaction), NUPR1 silencing, LCN2 knockdown, ferroptosis markers (GSH/GSSG, Fe2+)\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and m6A assay linking WTAP to NUPR1 mRNA stability, functional downstream LCN2/ferroptosis validation, single lab\",\n      \"pmids\": [\"37477758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUPR1 promotes FTH1 transcription in HCC cells (via the circPIAS1/miR-455-3p/NUPR1/FTH1 axis), enhancing iron storage and conferring ferroptosis resistance. CircPIAS1 sequesters miR-455-3p to upregulate NUPR1.\",\n      \"method\": \"RNA immunoprecipitation, luciferase reporter assays, ChIP (NUPR1 on FTH1 promoter), FISH, NUPR1 inhibitor ZZW-115, ferroptosis assays, xenograft models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming NUPR1 binding to FTH1 promoter with functional ferroptosis validation, single lab\",\n      \"pmids\": [\"38802795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUPR1 promotes PPAR-α signaling via the UPR, protecting liver from lipotoxic injury. NUPR1 loss-of-function in mice fed high-fat diet results in impaired UPR activation and reduced PPAR-α signaling, leading to increased hepatic steatosis.\",\n      \"method\": \"Nupr1-/- mice on high-fat diet, UPR pathway analysis, PPAR-α signaling assays, patient liver biopsy analysis, immunohistochemistry, mRNA analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with pathway mechanistic validation, single lab\",\n      \"pmids\": [\"33566371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUPR1 mediates METH-induced pulmonary arterial smooth muscle cell (PASMC) phenotypic conversion from contractile to synthetic by activating STIM1 expression, which opens store-operated calcium entry (SOCE) channels, promoting Ca2+ influx and pulmonary artery remodeling.\",\n      \"method\": \"NUPR1 expression analysis in human/mouse lung specimens, PASMC NUPR1 knockdown/overexpression, STIM1 expression assays, Ca2+ influx (SOCE) measurement, pulmonary artery remodeling histology, right ventricular systolic pressure measurement\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STIM1-SOCE mechanistic link established by gain/loss-of-function with Ca2+ measurement, single lab\",\n      \"pmids\": [\"38347241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Amphipathic helical peptides bind to NUPR1 around Ala33 and C-terminus residues (low micromolar Kd ~3 µM), inhibiting NUPR1-RING1B interaction in cellulo. The Thr68Gln mutant of NUPR1 does not interact with these peptides.\",\n      \"method\": \"Fluorescence, circular dichroism, NMR, ITC, docking/MD simulations, proximity ligation assays (in cellulo for NUPR1-RING1B interaction inhibition), site-directed mutagenesis (Thr68Gln)\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR + ITC + mutagenesis + in cellulo PLA, single lab with multiple orthogonal biophysical methods\",\n      \"pmids\": [\"29530795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of NUPR1 (p8) in mice results in delayed LHB (luteinizing hormone beta subunit) expression during gonadotroph development, ovarian maturation delay (absence of corpora lutea at 8 weeks), and age-related testicular germ cell loss resembling Sertoli-cell-only syndrome, demonstrating a role for NUPR1 in temporal regulation of LHB and gonadal function.\",\n      \"method\": \"Nupr1-/- mouse model, RT-qPCR for LHB/FSHB/GATA2/CGA/TSH expression at embryonic time points, gonadal histology, corpora lutea assessment\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with developmental phenotype characterization at multiple time points, single lab\",\n      \"pmids\": [\"18495683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AP-1 (via JUN binding sites) transcriptionally regulates NUPR1 in response to nickel exposure. Knockdown of JUN or FOS suppresses NUPR1 induction by Ni. Deletion of the upstream JUN binding site in the NUPR1 promoter reduces promoter activity.\",\n      \"method\": \"Luciferase reporter assay with NUPR1 promoter, JUN binding site deletion (site-directed mutagenesis), JUN/FOS knockdown experiments, NUPR1 promoter cloning\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis and epistasis by transcription factor knockdown, single lab\",\n      \"pmids\": [\"33649793\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUPR1 is a small, intrinsically disordered nuclear protein that functions as a stress-inducible transcriptional coregulator and chromatin-associated factor; it drives ferroptosis resistance by transcriptionally upregulating LCN2 (reducing iron accumulation) and FTH1 (enhancing iron storage), binds and inhibits PARP1 to protect against hyperPARylation-dependent cell death, promotes autolysosomal efflux by inducing SNAP25/VAMP8 SNARE complex formation, undergoes importin α3-mediated nuclear translocation regulated by phosphorylation of Thr68 in its NLS, and engages multiple chromatin partners (including p53/p300, MSL1/53BP1, RING1B, PADI4, PKP1, SREBP1, eIF2α, and AhR) via a conserved hydrophobic hot spot around Ala33 and Thr68 to modulate DNA repair, UPR resolution, lipogenesis, EMT, and stress granule formation via liquid-liquid phase separation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUPR1 is a small, intrinsically disordered, stress-inducible nuclear factor that acts as a transcriptional coregulator and chromatin-associated hub coordinating cell survival under genotoxic, metabolic, and ER stress [#0, #10]. A central output of NUPR1 is protection against regulated cell death: it transcriptionally upregulates the iron-handling genes LCN2 (limiting iron accumulation and oxidative damage) and FTH1 (enhancing iron storage) to confer ferroptosis resistance [#0, #38], and it binds and inhibits PARP1 in the nucleus to prevent hyperPARylation-driven, non-canonical Parthanatos and mitochondrial catastrophe [#11]. NUPR1 also sustains autophagic and lysosomal homeostasis, transcriptionally inducing the SNARE protein SNAP25 that complexes with VAMP8 to maintain autolysosomal efflux [#1] and activating TFE3 to preserve autophagic flux [#20]. Mechanistically, NUPR1 engages partners through a conserved disordered ('fuzzy') hydrophobic hot spot around Ala33, which mediates low-micromolar binding to chromatin and repair-associated factors including MSL1, RING1B, PADI4, and PKP1 [#4, #5, #22, #23], while phosphorylation of Thr68 within its nuclear localization signal triggers a conformational switch that disrupts importin α3 binding and gates its nuclear translocation [#17, #6]. In the nucleus NUPR1 stimulates SUMOylation of DNA damage response proteins [#7], cooperates with p53/p300 to drive p21 transcription [#2], and regulates DNMT1-dependent DNA methylation to modulate oncogene-induced senescence [#13, #14]. Its disordered nature also enables liquid-liquid phase separation required for stress granule formation in KrasG12D-driven pancreatic cancer [#21]. Through these activities NUPR1 broadly supports tumor cell survival, lipogenesis via SREBP1 [#28], and EMT, and it is the pharmacological target of the inhibitor ZZW-115, which blocks its nuclear import and triggers death of cancer cells [#6, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established NUPR1 as a developmental transcriptional regulator in vivo and as a chromatin-associated partner of p53/p300, framing it as a stress-responsive transcriptional coregulator rather than a passive marker.\",\n      \"evidence\": \"Nupr1-/- mouse gonadal development phenotyping; Co-IP, p21-promoter ChIP and chemoresistance assays in cancer cells\",\n      \"pmids\": [\"18495683\", \"18690848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding versus adaptor role on the p21 promoter not resolved\", \"Structural basis of the p53/p300 complex undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified MSL1 as a NUPR1 partner and placed NUPR1 as a negative regulator of MSL1/53BP1-dependent DNA repair, linking it to the genotoxic stress response.\",\n      \"evidence\": \"Protein interaction assays, cell-based DNA repair assays after gamma-irradiation, 53BP1 knockdown\",\n      \"pmids\": [\"19650074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface not mapped at this stage\", \"Mechanism of repair inhibition unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected NUPR1 to metabolic and DNA-methylation control of cell fate, showing it protects against metabolic-stress death via AURKA and chemoresistance via PI3K/Akt-phospho-p21, and is itself a TGFβ/SMAD transcriptional target.\",\n      \"evidence\": \"Transcriptome profiling, RNAi/overexpression, subcellular fractionation of p21, Akt-inhibitor experiments, SMAD ChIP and 5'-UTR reporter assays\",\n      \"pmids\": [\"22899799\", \"22858377\", \"22738338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect regulation of AURKA unclear\", \"How NUPR1 couples to Akt mechanistically not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the first quantitative biophysical view of NUPR1, showing it binds MSL1 and damaged DNA through a disordered 'fuzzy' interface, defining its mode of action as an intrinsically disordered interaction hub.\",\n      \"evidence\": \"ITC, fluorescence, NMR with in-nucleus Co-IP and cisplatin survival assays; promoter reporter assays for Ccna2/Tcf19 in beta cells\",\n      \"pmids\": [\"24205110\", \"23900510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the bound state not solved (remains disordered)\", \"Generality of the fuzzy mode across partners not yet shown at this point\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended NUPR1's role to oncogene-induced senescence and tumor invasion, showing DNMT1/DNA-methylation control of Kras-driven senescence and Ca2+-dependent regulation of invasion via granulin.\",\n      \"evidence\": \"Nupr1-/- KrasG12D mouse models, methylation analysis, 5-aza treatment; invasion assays with Ca2+ signaling inhibition and granulin promoter binding\",\n      \"pmids\": [\"26617245\", \"24902898\", \"26173068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNMT1 promoter occupancy not established\", \"Mechanism linking NUPR1 to Ca2+ signaling undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the NUPR1 interaction hot spot to the Ala33 hydrophobic patch (RING1B binding) and defined a transcriptional autophagy mechanism (SNAP25/VAMP8), unifying its structural mode with a concrete cell-biological output.\",\n      \"evidence\": \"NMR mapping, ITC, Ala33Gln mutagenesis, in cellulo ligation assays for RING1B; RNAi, Co-IP of SNAP25/VAMP8 and autophagy flux assays\",\n      \"pmids\": [\"28720707\", \"29130426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same hot spot mediates all partner interactions not yet generalized\", \"Transcriptional versus non-transcriptional contribution to autolysosomal efflux not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that NUPR1 loss causes mitochondrial failure and ER-stress-dependent programmed necrosis, establishing NUPR1 as a guardian of mitochondrial integrity during ER stress.\",\n      \"evidence\": \"Knockdown with mitochondrial membrane potential/OXPHOS/ROS assays, mitochondria-ER imaging, ER-stress inducers, acute pancreatitis model, Nec-1/Z-VAD rescue\",\n      \"pmids\": [\"30451898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between NUPR1 and mitochondrial maintenance not identified\", \"Transcriptional targets driving ER-stress resolution incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified ZZW-115 as a NUPR1 inhibitor that binds the Thr68/NLS region and blocks importin-mediated nuclear import, providing a druggable mechanism and a tool to dissect nuclear functions.\",\n      \"evidence\": \"ITC/fluorescence binding, modeling, nuclear translocation and necroptosis assays, xenografts; helical-peptide inhibitors of NUPR1-RING1B with Thr68Gln mutants\",\n      \"pmids\": [\"30920390\", \"29530795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Off-target effects of ZZW-115 not fully excluded\", \"Which downstream functions are import-dependent not delineated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the import-gating mechanism at residue level — Thr68 phosphorylation drives a coil-to-turn switch impairing importin α3 binding — and revealed NUPR1 directly stimulates SUMOylation of DDR proteins, defining a biochemical nuclear activity.\",\n      \"evidence\": \"NMR conformational analysis, ITC of NLS-Impα3, phospho-mimetic mutants; interactome MS, cell-free SUMOylation reconstitution with recombinant NUPR1; PKP1 binding by NMR/ITC/PLA\",\n      \"pmids\": [\"32933064\", \"32780723\", \"33385445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Thr68 phosphorylation not identified\", \"Mechanism by which NUPR1 stimulates the SUMO machinery unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated NUPR1 as a master suppressor of regulated cell death, showing it inhibits PARP1 to block Parthanatos and transcriptionally controls LCN2/FTH1 iron handling to confer ferroptosis resistance.\",\n      \"evidence\": \"Proteomic interactome, NUPR1-PARP1 Co-IP and in vitro PARP1 activity assays with mutants, olaparib/NMN rescue; NanoString/shRNA/conditional KO and LCN2 re-expression; FTH1 promoter ChIP; TFAM-rescue ferroptosis assays\",\n      \"pmids\": [\"35869257\", \"33510144\", \"38802795\", \"34599149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/site of PARP1 inhibition not structurally defined\", \"How NUPR1 selects between ferroptosis, Parthanatos and necrosis outputs unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Broadened NUPR1's regulatory reach to lipogenesis, autophagy and UPR resolution, and to additional chromatin partners, positioning it as an integrator of metabolic and proteostatic stress.\",\n      \"evidence\": \"SREBP1 Co-IP and FASN/lipid assays; TFE3 activity and autophagy assays; AhR Co-IP and autophagic degradation; eIF2α Co-IP/PLA and nascent-synthesis assays; PPAR-α/UPR analysis in KO mice\",\n      \"pmids\": [\"36307402\", \"35462576\", \"36258210\", \"33403797\", \"33566371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect engagement of each metabolic partner varies in rigor\", \"Whether these interactions share the Ala33 hot spot not tested for all partners\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized the Ala33 hydrophobic-patch binding mode to PADI4 and detailed transcriptional/epigenetic control of NUPR1 itself, including SETD4-mediated H3K27me3 repression and m6A-dependent stabilization.\",\n      \"evidence\": \"NMR/ITC/PLA for PADI4 with Ala33 mutagenesis; SETD4 ChIP for H3K27me3 at the NUPR1 locus; WTAP/eIF3A m6A and mRNA-stability assays\",\n      \"pmids\": [\"36858171\", \"37879429\", \"37477758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of NUPR1-PADI4 binding not established\", \"Interplay between epigenetic and post-transcriptional control of NUPR1 levels unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed NUPR1 undergoes liquid-liquid phase separation required for stress granule formation in KrasG12D pancreatic cancer, providing a biophysical basis for its disordered-protein stress functions.\",\n      \"evidence\": \"In vitro LLPS assays, stress granule imaging, ZZW-115 inhibition, NUPR1 overexpression, KC mouse model with caspase-3 readouts\",\n      \"pmids\": [\"38360999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partner RNAs/proteins co-condensing with NUPR1 not identified\", \"Link between LLPS and the transcriptional/chromatin functions not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Embedded NUPR1 in the tumor microenvironment and stress-hormone signaling, showing lactate/histone-lactylation induces it in macrophages to promote M2 polarization and that glucocorticoid-receptor signaling drives NUPR1-dependent EMT.\",\n      \"evidence\": \"scRNA-seq, histone-lactylation analysis and ERK/JNK assays in macrophages; NR3C1 promoter regulation and SNAI2/EMT in stress mouse models; FTO/YTHDF2 m6A stabilization of NUPR1 mRNA\",\n      \"pmids\": [\"40305758\", \"40654365\", \"40334546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic versus microenvironmental contributions not separated\", \"Mechanism by which NUPR1 suppresses ERK/JNK undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUPR1's disordered structure, Thr68-gated nuclear import, phase separation, and partner-selection at the Ala33 hot spot are integrated to choose among its many context-specific outputs (ferroptosis, Parthanatos, autophagy, lipogenesis, EMT) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of NUPR1 in any partner complex (interface remains 'fuzzy')\", \"Upstream kinase and signaling that control Thr68 phosphorylation unknown\", \"Determinants of partner/output selection from a single hydrophobic hot spot undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 26, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 4, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 3, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 22, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5, 11, 17, 18, 22, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 11, 10, 30]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 20, 19]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 18, 39]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 26, 38]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"MSL1\", \"RING1B\", \"PADI4\", \"PKP1\", \"SREBP1\", \"EIF2S1\", \"AHR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}