{"gene":"HMGB3","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1986,"finding":"HMG-2a (HMGB3) protein binds preferentially to DNA regions of reduced thermodynamic stability, showing highest affinity for (dI)·(dC) and (A+T)-rich polynucleotides and (A+T)-rich restriction fragments from multiple genomes, establishing sequence-independent but structure-selective DNA binding at physiological ionic strength.","method":"Nitrocellulose filter binding assay with immunopurified protein and synthetic polynucleotides/restriction fragments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro binding assay with purified protein, single lab, single method","pmids":["3003066"],"is_preprint":false},{"year":1998,"finding":"HMG4 (HMGB3) encodes a 200-amino-acid nuclear protein of the HMG1/2 family, highly expressed in the embryo and barely detectable in adult tissues; the human gene maps to chromosome Xq28.","method":"cDNA cloning, sequencing, Northern blot expression analysis, chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA identification and chromosomal mapping with multiple methods; single lab","pmids":["9598312"],"is_preprint":false},{"year":2003,"finding":"Enforced retroviral expression of Hmgb3 in mouse bone marrow stem cells inhibits B-cell and myeloid differentiation, establishing a functional role for Hmgb3 in suppressing lineage commitment from hematopoietic progenitors.","method":"Retroviral overexpression in mouse bone marrow cells; GFP knock-in reporter to identify Hmgb3-expressing cells; long-term repopulation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function retroviral overexpression with defined in vivo differentiation phenotype, replicated by same group in follow-up loss-of-function study","pmids":["12714519"],"is_preprint":false},{"year":2004,"finding":"Hmgb3-deficient (Hmgb3−/Y) mice have normal HSC numbers but produce fewer CLPs and CMPs; Hmgb3−/Y HSCs show increased Gata-2 and c-myb mRNA levels and enhanced BrdU incorporation, indicating Hmgb3 is required for proper HSC expansion into lymphoid and myeloid progenitors.","method":"Knockout mouse generation; flow cytometry; BrdU incorporation; qRT-PCR","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with multiple orthogonal readouts (cell numbers, proliferation, gene expression), replicated in follow-up study","pmids":["15358624"],"is_preprint":false},{"year":2006,"finding":"Hmgb3-deficient HSCs exhibit constitutive activation of canonical Wnt signaling with increased Dvl1 expression, and show faster HSC recovery after 5-fluorouracil treatment; this positions Hmgb3 as a negative regulator of Wnt-driven HSC self-renewal.","method":"Knockout mouse; Wnt pathway gene expression analysis; 5-FU stress recovery assays; flow cytometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined genetic epistasis (Hmgb3 KO → Dvl1 up → Wnt activation → enhanced self-renewal) with functional recovery assay, single lab with multiple orthogonal methods","pmids":["16945912"],"is_preprint":false},{"year":2012,"finding":"miR-206 directly binds a functional site in the 3'UTR of Hmgb3 mRNA and represses its expression during skeletal muscle regeneration; Hmgb3 mRNA and protein decrease concurrently with miR-206 upregulation in regenerating muscle fibers.","method":"3'UTR luciferase reporter assay; qRT-PCR and Western blot in single regenerating muscle fibers from dystrophic and acutely damaged mouse models","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated 3'UTR binding site with functional reporter assay and protein-level confirmation in physiological model, single lab","pmids":["22912879"],"is_preprint":false},{"year":2013,"finding":"miR-205 directly binds two sites in the 3'UTR of HMGB3 and represses its expression; knockdown of HMGB3 by siRNA reduces proliferation and invasion of breast cancer cells, phenocopying miR-205 overexpression.","method":"Dual-luciferase reporter assay; Western blotting; WST-1 proliferation assay; in vitro invasion assay; siRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miRNA-target binding with functional KD phenotype, two orthogonal methods, single lab","pmids":["24098490"],"is_preprint":false},{"year":2016,"finding":"HMGB3 knockdown by siRNA in gastric cancer cells inhibits proliferation, induces G0/G1 arrest partly via p53/p21 upregulation, decreases Bcl-2/Bax ratio, and reduces migration/invasion by downregulating MMP2 and MMP9; HMGB3 knockdown also sensitizes cells to cisplatin and paclitaxel.","method":"siRNA knockdown; MTT assay; flow cytometry; wound scratch and transwell assays; Western blot","journal":"Medical science monitor","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with multiple orthogonal phenotypic readouts and pathway markers, single lab","pmids":["27774979"],"is_preprint":false},{"year":2016,"finding":"miR-27b directly regulates HMGB3 expression by binding its 3'UTR; re-expression of miR-27b in tamoxifen-resistant MCF-7 cells reduces HMGB3 protein, sensitizes cells to tamoxifen, and inhibits invasion and EMT-like properties; silencing HMGB3 alone partially phenocopies these effects.","method":"Dual luciferase assay; Western blot; MSP assay; qRT-PCR; functional cell assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated direct miRNA-3'UTR binding plus functional rescue, single lab, multiple orthogonal methods","pmids":["27363334"],"is_preprint":false},{"year":2017,"finding":"HMGB3 promotes proliferation and migration in colorectal cancer by activating the WNT/β-catenin pathway, increasing downstream c-Myc and MMP7 expression.","method":"siRNA knockdown; overexpression; in vitro proliferation and migration assays; Western blot for β-catenin, c-Myc, MMP7","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with pathway protein readouts, single lab, multiple methods","pmids":["28678825"],"is_preprint":false},{"year":2017,"finding":"miR-205-5p directly regulates HMGB3 in prostate cancer cells as confirmed by luciferase reporter assay; knockdown of HMGB3 by siRNA reduces prostate cancer cell aggressiveness.","method":"Luciferase reporter assay; siRNA knockdown; functional cell assays","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated direct miRNA-target relationship with functional KD, single lab","pmids":["29196733"],"is_preprint":false},{"year":2018,"finding":"Hmgb3 promotes uterine stromal cell differentiation (decidualization) by upregulating pleiotrophin (Ptn); silencing Ptn blocks Hmgb3-induced Prl8a2 expression while Ptn overexpression rescues Hmgb3 siRNA-mediated repression of Prl8a2.","method":"In situ hybridization; siRNA knockdown; overexpression; qRT-PCR; rescue experiments in mouse uterine stromal cells","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiment placing Hmgb3 upstream of Ptn in stromal cell differentiation, single lab","pmids":["30081728"],"is_preprint":false},{"year":2018,"finding":"miR-200b-3p and miR-200c-3p directly bind the 3'UTR of HMGB3 and inhibit its expression in glioblastoma cells; HMGB3 knockdown reduces MAPK phosphorylation (ERK1/2, p38, JNK), implicating HMGB3 as an activator of the MAPK signaling pathway.","method":"Luciferase reporter assay; qRT-PCR; Western blot; siRNA knockdown; MTT and sphere assays; wound healing and transwell assays","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miRNA-target binding plus downstream MAPK pathway readout via Western blot, single lab","pmids":["30232806"],"is_preprint":false},{"year":2019,"finding":"HMGB3 interacts with HIF1α; HMGB3 silencing reduces HIF1α-driven mammosphere formation, cancer stem cell markers (Nanog, SOX2, OCT-4), and CD44+/CD24− levels in breast cancer cells, as validated by dual luciferase assay.","method":"Dual luciferase assay; CCK-8 assay; mammosphere assay; flow cytometry; xenograft mouse model; qRT-PCR and Western blot","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction validated by luciferase assay with multiple functional readouts including in vivo model, single lab","pmids":["31213919"],"is_preprint":false},{"year":2019,"finding":"miR-532-5p directly targets the 3'UTR of HMGB3 and negatively regulates its expression; HMGB3 mediates Wnt/β-catenin pathway activation, and restoration of HMGB3 partially reverses the anti-tumor effects of miR-532-5p overexpression in bladder cancer cells.","method":"Dual luciferase reporter assay; Western blot; functional cell assays; rescue experiments","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated direct miRNA-3'UTR binding with pathway and functional rescue, single lab","pmids":["30639441"],"is_preprint":false},{"year":2019,"finding":"HMGB3 directly binds the hTERT promoter region (−902 to −321) and transcriptionally upregulates hTERT, thereby promoting radioresistance; HMGB3 knockdown inhibits DNA damage repair and increases γH2AX foci, while HMGB3 knockdown-mediated radiosensitization is reversed by hTERT overexpression.","method":"Streptavidin-agarose pulldown; LC/MS; luciferase reporter assay; γH2AX foci analysis; rescue assays; xenograft mouse model","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct promoter binding confirmed by streptavidin pulldown + MS + luciferase, epistasis via rescue, in vivo validation; single lab but multiple orthogonal methods","pmids":["33187536"],"is_preprint":false},{"year":2020,"finding":"HMGB3 promotes NSCLC proliferation and invasion by activating the ERK/MAPK signaling pathway; HMGB3 overexpression increases p-ERK1/2 levels and its effects are reversed by the ERK/MAPK inhibitor PD98059.","method":"Luciferase reporter assay; Western blot for ERK/MAPK phosphorylation; ERK inhibitor rescue; in vitro proliferation/invasion assays","journal":"International journal of general medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway activation confirmed by phospho-Western and inhibitor rescue, single lab","pmids":["33328759"],"is_preprint":false},{"year":2020,"finding":"LncRNA PITPNA-AS1 stabilizes HMGB3 mRNA by recruiting RNA-binding protein TAF15 in the cytosol of LUSC cells; PITPNA-AS1 depletion reduces HMGB3 mRNA stability and suppresses LUSC cell proliferation and migration.","method":"RNA immunoprecipitation; mRNA stability assay; subcellular fractionation; rescue experiments; functional cell assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-confirmed TAF15-HMGB3 mRNA interaction with mRNA stability readout, single lab","pmids":["32871048"],"is_preprint":false},{"year":2020,"finding":"HMGB3 silencing inhibits NSCLC cell growth and invasion partly by inhibiting β-catenin, MMP7, and c-Myc expression in the Wnt pathway.","method":"siRNA knockdown; in vitro growth and invasion assays; Western blot for Wnt pathway proteins; xenograft model","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway protein readouts and in vivo confirmation, single lab","pmids":["32386184"],"is_preprint":false},{"year":2021,"finding":"HMGB3 functions as an RNA-binding protein that binds to the TIM-TAM sequence-structure in HIV-1 tat mRNA; HMGB3 knockdown increases Tat transactivation and translation as well as productive HIV-1 infection, whereas overexpression has the opposite effect.","method":"Affinity purification coupled with mass spectrometry; luciferase-based reporter assays; RNA footprinting; dual-color HIV reporter virus infection; knockdown and overexpression","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — AP-MS identification plus luciferase reporter and footprinting confirming direct mRNA binding and functional consequence, single lab","pmids":["34194479"],"is_preprint":false},{"year":2021,"finding":"HMGB3-containing nuclear exosomes (nEXOs) derived from micronuclei of NPC cells are ingested by HUVECs and accelerate angiogenesis in vitro and in vivo in a zebrafish xenograft model; HMGB3 secretion is associated with micronuclei formation.","method":"Western blot; flow cytometry; HUVEC tube formation assay; zebrafish angiogenesis xenograft model; nEXO isolation and characterization","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined exosomal secretion mechanism with in vitro and in vivo angiogenesis functional assays, single lab","pmids":["34050127"],"is_preprint":false},{"year":2021,"finding":"HMGB3 inhibition by miR-142-3p or shRNA induces apoptosis in breast cancer cells via increased ROS accumulation, decreased mitochondrial membrane potential (MMP), disruption of autophagy (altered LC3, cleaved PARP, Bcl-xL), and reduced phospho-mTOR and STAT3.","method":"3'UTR luciferase reporter assay; ROS detection (DHE dye); MitoTracker for MMP; Western blot for autophagy and apoptosis markers; zebrafish xenograft for in vivo metastasis","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miRNA-target binding with multiple orthogonal mechanistic readouts, single lab","pmids":["35753437"],"is_preprint":false},{"year":2022,"finding":"HMGB3 directly interacts with PARP1; this interaction is enhanced under DNA damage conditions and blocked by olaparib. HMGB3 loss causes PARP1 trapping at DNA lesions and inhibits PARylation activity of PARP1, resulting in increased DNA damage response and apoptosis.","method":"Co-immunoprecipitation; Western blot; functional assays in olaparib-resistant/sensitive cells; xenograft mouse model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP confirming direct HMGB3-PARP1 interaction with defined mechanistic consequence (PARP1 trapping, reduced PARylation), supported by in vivo xenograft, single lab with multiple orthogonal methods","pmids":["35332131"],"is_preprint":false},{"year":2022,"finding":"SOX9 activates NANOG gene transcription by binding a conserved cis-regulatory element (−573 to −568) in the NANOG promoter; HMGB3 acts as a co-activator partner of SOX9 for this transactivation, interacting with SOX9 predominantly via the HMG Box A domain of HMGB3.","method":"Reporter gene transcription assays; protein-binding assays (Co-IP); ChIP for SOX9 binding sites; siRNA/overexpression of SOX9 and HMGB3","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms SOX9-HMGB3 interaction; luciferase reporter and domain mapping define functional interface, single lab","pmids":["36541373"],"is_preprint":false},{"year":2022,"finding":"SYT7 interacts with BRCA1 to inhibit HMGB3 ubiquitination, thereby stabilizing HMGB3 protein levels in thyroid cancer cells; HMGB3 knockdown reverses the pro-tumorigenic effects of SYT7 overexpression.","method":"Co-IP assay; GeneChip transcriptomics; UbiBrowser database prediction; functional cell assays; rescue experiments","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms SYT7-BRCA1-HMGB3 interaction and ubiquitination regulation, single lab","pmids":["35073278"],"is_preprint":false},{"year":2022,"finding":"HDAC3 promotes HMGB3 expression in breast cancer by epigenetically repressing miR-130a-3p, which directly targets HMGB3; this axis facilitates immune escape by suppressing CD8+/CD69+/PD-1+ T cell cytotoxicity against cancer cells.","method":"qRT-PCR; Western blot; correlation analysis; functional cell viability, migration, EMT, and apoptosis assays; CD8+ T cell co-culture cytotoxicity assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined HDAC3→miR-130a-3p→HMGB3 regulatory axis with functional immune readout, single lab","pmids":["33727043"],"is_preprint":false},{"year":2023,"finding":"HMGB3 promotes ovarian cancer stemness, proliferation, and metastasis through activation of the MAPK/ERK signaling pathway, as established by RNA-seq identifying HMGB3-regulated pathways and Western blot confirmation; these effects were also verified in a xenograft model.","method":"RNA sequencing; Western blot for MAPK/ERK pathway proteins; MTT, clonogenic, EdU, and Transwell assays; xenograft mouse model","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq pathway identification with Western blot confirmation and in vivo validation, single lab","pmids":["37328851"],"is_preprint":false},{"year":2024,"finding":"HMGB3 directly binds N2-nBu-dG-containing duplex DNA (minor-groove alkylguanine lesion) in vitro and promotes repair of this lesion in human cells; HMGB3 shows stereospecific binding, favoring trans-N2-BPDE-dG over cis-N2-BPDE-dG; genetic ablation of HMGB3 reduces repair of trans-N2-BPDE-dG but not cis-N2-BPDE-dG.","method":"Photo-cross-linking coupled with quantitative mass spectrometry proteomics; in vitro direct DNA-binding assay; HMGB3 knockout cell lines; DNA repair assays; cell viability assay with BPDE treatment","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted binding confirmed by photo-crosslinking MS, stereospecific mechanistic distinction with KO repair assays; multiple orthogonal methods in single rigorous study","pmids":["39101269"],"is_preprint":false},{"year":2024,"finding":"Exosomal HMGB3 from silica-exposed macrophages activates STAT3/MAPK(ERK1/2 and p38)/NF-κB signaling pathways in recipient monocytes/macrophages and promotes their migration via CCR2, driving M1 macrophage polarization and pulmonary inflammation.","method":"Immunofluorescence; flow cytometry; transwell migration assay; RT-PCR; ELISA; Western blot for pathway activation","journal":"Particle and fibre toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exosomal transfer mechanism with pathway activation Western blots and functional migration assay, single lab","pmids":["38454505"],"is_preprint":false},{"year":2024,"finding":"Cytoplasmic HMGB3 (following hypoxia-induced translocation from nucleus) activates TLR3/NF-κB signaling; extracellular HMGB3 interacts with transmembrane TREM1 receptor in papillary thyroid cancer cells, promoting cancer progression.","method":"Immunofluorescence for subcellular localization; co-immunoprecipitation; dual-luciferase reporter assay; Western blot; flow cytometry; IPA pathway analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms HMGB3-TREM1 interaction; luciferase confirms TLR3/NF-κB activation; localization by IF; single lab","pmids":["38197217"],"is_preprint":false},{"year":2024,"finding":"ELAVL1 (HuR) directly interacts with HMGB3 mRNA and increases its stability; HMGB3 overexpression activates β-catenin signaling and promotes glycolysis in nasopharyngeal carcinoma cells; β-catenin inhibitor FH535 suppresses HMGB3-driven glycolysis.","method":"RNA pulldown assay; RIP assay; TOPFlash/FOPFlash reporter assay; ECAR measurement; glucose/lactate assay kits; Western blot; xenograft model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and RNA pulldown confirm direct ELAVL1-HMGB3 mRNA interaction; functional glycolysis and β-catenin pathway readouts; single lab","pmids":["39390359"],"is_preprint":false},{"year":2024,"finding":"HMGB3 contributes to anti-PD-1 resistance in TNBC by inhibiting IFN-γ-driven ferroptosis; HMGB3 overexpression inhibits STAT1 phosphorylation and IRF1 expression upon IFN-γ treatment while activating STAT3, and increases ferroptosis-inhibitory proteins SLC7A11, GPX4, and SLC3A2.","method":"siRNA knockdown; lentiviral overexpression; Western blot for STAT1/STAT3/IRF1/ferroptosis proteins; co-IP for STAT1-STAT3 interaction; in vivo anti-PD-1 treatment mouse models; immunohistochemistry","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mechanism (HMGB3 suppresses IFN-γ/STAT1 axis, activates STAT3, upregulates ferroptosis inhibitors) with Co-IP and in vivo validation; single lab","pmids":["39660968"],"is_preprint":false},{"year":2025,"finding":"HMGB3 is involved in processing DNA interstrand crosslinks (ICLs) and DNA double-strand breaks (DSBs) in human cells; unlike HMGB1, HMGB3 does not play a role in nucleotide excision repair (NER).","method":"HMGB3 knockout human cell lines; UV damage/NER assay; mutagenesis assays; metaphase spreads; DNA repair foci formation assays; TagSeq analysis","journal":"Genes","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — clean KO cell lines with multiple orthogonal repair assays distinguishing ICL, DSB, and NER roles; single lab","pmids":["41009989"],"is_preprint":false},{"year":2025,"finding":"HMGB3 recruits SSBP1 and induces its nuclear translocation, reprogramming mitochondrial metabolism; this elevates cytoplasmic ROS and activates PI3K/Akt signaling by downregulating PTEN, promoting LUAD cell proliferation, migration, invasion, EMT, and brain metastasis.","method":"Co-immunoprecipitation combined with mass spectrometry; Western blot; gain/loss-of-function; in vivo brain metastasis mouse model; scRNA-seq and bulk RNA-seq; immunohistochemistry","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifies SSBP1 as interaction partner; mechanistic epistasis (HMGB3→SSBP1 nuclear translocation→mitochondrial remodeling→ROS→PTEN down→PI3K/Akt) confirmed by multiple methods; single lab","pmids":["41194553"],"is_preprint":false},{"year":2025,"finding":"TGIF2 transcriptionally upregulates HMGB3 in esophageal squamous cell carcinoma; HMGB3 activates TGF-β signaling by interacting with and regulating TLR3, promoting ESCC proliferation and metastasis.","method":"Luciferase reporter assay; chromatin immunoprecipitation; co-immunoprecipitation; RNA sequencing; Western blot; in vitro and in vivo functional assays","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms TGIF2 binding to HMGB3 promoter; Co-IP confirms HMGB3-TLR3 interaction; RNA-seq identifies downstream pathway; single lab","pmids":["41716633"],"is_preprint":false}],"current_model":"HMGB3 is a sequence-independent, chromatin-associated HMG-box protein that preferentially binds DNA regions of reduced stability and minor-groove alkyl-guanine lesions (facilitating their stereospecific repair via ICL and DSB pathways but not NER), acts as a transcriptional co-activator (e.g., cooperating with SOX9 to transactivate NANOG, and directly binding the hTERT promoter), interacts with PARP1 to modulate PARylation and DNA damage responses, binds the RNA-binding protein ELAVL1 and tat mRNA to regulate translation, recruits SSBP1 to reprogram mitochondrial metabolism, and in hematopoietic stem cells negatively regulates canonical Wnt/Dvl1 signaling to balance self-renewal versus differentiation; its overexpression in cancers promotes proliferation, invasion, radioresistance, and immunotherapy resistance through activation of Wnt/β-catenin, MAPK/ERK, and IFN-γ/STAT signaling axes, while being post-translationally regulated by SYT7/BRCA1-mediated ubiquitination and post-transcriptionally regulated by multiple miRNAs targeting its 3'UTR."},"narrative":{"mechanistic_narrative":"HMGB3 is an embryonically-enriched, X-linked HMG-box chromatin protein that binds DNA in a sequence-independent but structure-selective manner, favoring regions of reduced thermodynamic stability and (A+T)-rich tracts [PMID:3003066, PMID:9598312]. In hematopoiesis it restrains lineage commitment: enforced expression blocks B-cell and myeloid differentiation, while its loss reduces lymphoid and myeloid progenitor output and derepresses canonical Wnt signaling through elevated Dvl1, marking HMGB3 as a negative regulator of Wnt-driven HSC self-renewal versus differentiation [PMID:12714519, PMID:15358624, PMID:16945912]. At chromatin and DNA-damage sites HMGB3 binds minor-groove alkyl-guanine lesions stereospecifically and promotes their repair, and it participates in interstrand-crosslink and double-strand-break processing without contributing to nucleotide excision repair [PMID:39101269, PMID:41009989]; it directly interacts with PARP1, sustaining PARylation and preventing PARP1 trapping at lesions [PMID:35332131]. HMGB3 also acts as a transcriptional co-activator, partnering with SOX9 via its HMG Box A domain to transactivate NANOG and binding the hTERT promoter to drive telomerase expression and radioresistance [PMID:36541373, PMID:33187536]. Beyond the nucleus it functions as an RNA-binding protein that engages a structured element of HIV-1 tat mRNA to repress Tat translation [PMID:34194479], and its own mRNA is stabilized by ELAVL1/HuR and by lncRNA PITPNA-AS1/TAF15 [PMID:39390359, PMID:32871048]. In cancers HMGB3 is broadly overexpressed and promotes proliferation, invasion, stemness, and metabolic reprogramming through Wnt/β-catenin, MAPK/ERK, and PI3K/Akt axes and by recruiting SSBP1 to remodel mitochondrial metabolism [PMID:28678825, PMID:37328851, PMID:41194553], and it drives immune escape and anti-PD-1 resistance by suppressing the IFN-γ/STAT1 axis while activating STAT3 [PMID:33727043, PMID:39660968]. Its abundance is governed post-transcriptionally by numerous 3'UTR-targeting miRNAs and post-translationally by SYT7/BRCA1-modulated ubiquitination [PMID:24098490, PMID:35073278].","teleology":[{"year":1986,"claim":"Established the biochemical nature of HMGB3 DNA binding, defining it as a structure-selective rather than sequence-specific reader of the genome.","evidence":"Nitrocellulose filter binding assays with immunopurified protein and synthetic polynucleotides","pmids":["3003066"],"confidence":"Medium","gaps":["No structural model of the protein-DNA complex","Binding tested in vitro only, not on chromatin in cells"]},{"year":1998,"claim":"Defined HMGB3 molecularly as an HMG1/2-family nuclear protein with embryo-restricted expression and an Xq28 location, setting its developmental context.","evidence":"cDNA cloning, Northern blot, and chromosomal mapping","pmids":["9598312"],"confidence":"Medium","gaps":["Expression pattern not linked to a function","Adult tissue roles undefined"]},{"year":2006,"claim":"Resolved HMGB3's role in hematopoiesis, showing it balances stem-cell self-renewal against differentiation by restraining canonical Wnt signaling.","evidence":"Retroviral overexpression, knockout mice, BrdU/flow cytometry, Wnt pathway analysis, and 5-FU recovery assays","pmids":["12714519","15358624","16945912"],"confidence":"High","gaps":["Molecular mechanism linking HMGB3 to Dvl1 levels unresolved","Direct chromatin targets in HSCs not identified"]},{"year":2018,"claim":"Extended HMGB3 transcriptional control to other differentiation programs, placing it upstream of pleiotrophin in uterine decidualization.","evidence":"siRNA/overexpression rescue experiments in mouse uterine stromal cells","pmids":["30081728"],"confidence":"Medium","gaps":["Whether HMGB3 binds the Ptn locus directly is untested","Generalizability beyond uterine stroma unknown"]},{"year":2019,"claim":"Defined direct transcriptional targets, showing HMGB3 binds the hTERT promoter to drive telomerase and radioresistance.","evidence":"Streptavidin pulldown + LC/MS, luciferase reporter, γH2AX foci, and hTERT rescue in xenografts","pmids":["33187536"],"confidence":"High","gaps":["Co-factors at the hTERT promoter not defined","Relationship to its structure-selective binding unclear"]},{"year":2021,"claim":"Revealed an RNA-binding function, identifying HMGB3 as a repressor of HIV-1 Tat translation via a structured tat mRNA element.","evidence":"AP-MS, RNA footprinting, luciferase reporters, and HIV reporter-virus infection with knockdown/overexpression","pmids":["34194479"],"confidence":"Medium","gaps":["Cellular mRNA targets of this RNA-binding activity not catalogued","Domain mediating RNA binding not mapped"]},{"year":2022,"claim":"Connected HMGB3 to the PARP1-dependent DNA damage response, showing it sustains PARylation and prevents PARP1 trapping.","evidence":"Reciprocal Co-IP, olaparib sensitivity assays, and xenografts","pmids":["35332131"],"confidence":"High","gaps":["Whether HMGB3 is a PARylation substrate or regulator is not distinguished","Recruitment kinetics to lesions undefined"]},{"year":2022,"claim":"Defined a transcriptional co-activator partnership, mapping the SOX9-HMGB3 interface to HMG Box A in NANOG activation.","evidence":"Co-IP, ChIP, domain-mapping, and luciferase reporter assays","pmids":["36541373"],"confidence":"Medium","gaps":["Structural basis of the SOX9-HMGB3 interface not solved","Genome-wide co-occupancy not mapped"]},{"year":2024,"claim":"Established a direct DNA-repair function with chemical precision, showing HMGB3 binds and promotes stereospecific repair of minor-groove alkylguanine lesions.","evidence":"Photo-cross-linking quantitative MS, in vitro binding, and repair assays in HMGB3-knockout cells","pmids":["39101269"],"confidence":"High","gaps":["Downstream repair factors recruited by HMGB3 not identified","Structural basis of stereoselectivity unresolved"]},{"year":2024,"claim":"Expanded HMGB3 into extracellular and signaling roles, showing secreted/translocated HMGB3 engages TLR3, TREM1, and STAT/MAPK/NF-κB cascades and drives immune escape and inflammation.","evidence":"Co-IP, luciferase reporters, exosome transfer assays, IFN-γ/anti-PD-1 mouse models, and pathway Western blots","pmids":["33727043","38454505","38197217","39660968","39390359"],"confidence":"Medium","gaps":["Receptor-binding determinants of extracellular HMGB3 not mapped","How a nuclear HMG protein reaches the cell surface mechanistically unclear"]},{"year":2025,"claim":"Delineated HMGB3's lesion-specific repair pathway membership and a mitochondrial metabolic reprogramming function via SSBP1.","evidence":"Knockout cell repair assays (ICL/DSB/NER discrimination), Co-IP/MS, and in vivo metastasis models","pmids":["41009989","41194553"],"confidence":"High","gaps":["Mechanistic link between SSBP1 nuclear translocation and mitochondrial remodeling incompletely defined","How HMGB3 selects ICL/DSB over NER pathways unresolved"]},{"year":null,"claim":"How HMGB3's distinct activities — structure-selective DNA binding, lesion repair, transcriptional co-activation, and RNA binding — are coordinated by a single protein, and what governs its subcellular partitioning between nucleus, cytoplasm, and extracellular space, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or domain-level model connecting DNA-, RNA-, and protein-binding activities","Triggers and machinery for nuclear-to-extracellular relocalization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,27,32]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[15,23]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[27,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,15,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[29,17]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[20,28,29]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[22,27,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[15,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9,26,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25,28,31]}],"complexes":[],"partners":["PARP1","SOX9","ELAVL1","SSBP1","TLR3","TREM1","HIF1A","TAF15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15347","full_name":"High mobility group protein B3","aliases":["High mobility group protein 2a","HMG-2a","High mobility group protein 4","HMG-4"],"length_aa":200,"mass_kda":23.0,"function":"Multifunctional protein with various roles in different cellular compartments. 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strength.\",\n      \"method\": \"Nitrocellulose filter binding assay with immunopurified protein and synthetic polynucleotides/restriction fragments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro binding assay with purified protein, single lab, single method\",\n      \"pmids\": [\"3003066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"HMG4 (HMGB3) encodes a 200-amino-acid nuclear protein of the HMG1/2 family, highly expressed in the embryo and barely detectable in adult tissues; the human gene maps to chromosome Xq28.\",\n      \"method\": \"cDNA cloning, sequencing, Northern blot expression analysis, chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA identification and chromosomal mapping with multiple methods; single lab\",\n      \"pmids\": [\"9598312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Enforced retroviral expression of Hmgb3 in mouse bone marrow stem cells inhibits B-cell and myeloid differentiation, establishing a functional role for Hmgb3 in suppressing lineage commitment from hematopoietic progenitors.\",\n      \"method\": \"Retroviral overexpression in mouse bone marrow cells; GFP knock-in reporter to identify Hmgb3-expressing cells; long-term repopulation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function retroviral overexpression with defined in vivo differentiation phenotype, replicated by same group in follow-up loss-of-function study\",\n      \"pmids\": [\"12714519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Hmgb3-deficient (Hmgb3−/Y) mice have normal HSC numbers but produce fewer CLPs and CMPs; Hmgb3−/Y HSCs show increased Gata-2 and c-myb mRNA levels and enhanced BrdU incorporation, indicating Hmgb3 is required for proper HSC expansion into lymphoid and myeloid progenitors.\",\n      \"method\": \"Knockout mouse generation; flow cytometry; BrdU incorporation; qRT-PCR\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with multiple orthogonal readouts (cell numbers, proliferation, gene expression), replicated in follow-up study\",\n      \"pmids\": [\"15358624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Hmgb3-deficient HSCs exhibit constitutive activation of canonical Wnt signaling with increased Dvl1 expression, and show faster HSC recovery after 5-fluorouracil treatment; this positions Hmgb3 as a negative regulator of Wnt-driven HSC self-renewal.\",\n      \"method\": \"Knockout mouse; Wnt pathway gene expression analysis; 5-FU stress recovery assays; flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic epistasis (Hmgb3 KO → Dvl1 up → Wnt activation → enhanced self-renewal) with functional recovery assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16945912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"miR-206 directly binds a functional site in the 3'UTR of Hmgb3 mRNA and represses its expression during skeletal muscle regeneration; Hmgb3 mRNA and protein decrease concurrently with miR-206 upregulation in regenerating muscle fibers.\",\n      \"method\": \"3'UTR luciferase reporter assay; qRT-PCR and Western blot in single regenerating muscle fibers from dystrophic and acutely damaged mouse models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated 3'UTR binding site with functional reporter assay and protein-level confirmation in physiological model, single lab\",\n      \"pmids\": [\"22912879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-205 directly binds two sites in the 3'UTR of HMGB3 and represses its expression; knockdown of HMGB3 by siRNA reduces proliferation and invasion of breast cancer cells, phenocopying miR-205 overexpression.\",\n      \"method\": \"Dual-luciferase reporter assay; Western blotting; WST-1 proliferation assay; in vitro invasion assay; siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miRNA-target binding with functional KD phenotype, two orthogonal methods, single lab\",\n      \"pmids\": [\"24098490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HMGB3 knockdown by siRNA in gastric cancer cells inhibits proliferation, induces G0/G1 arrest partly via p53/p21 upregulation, decreases Bcl-2/Bax ratio, and reduces migration/invasion by downregulating MMP2 and MMP9; HMGB3 knockdown also sensitizes cells to cisplatin and paclitaxel.\",\n      \"method\": \"siRNA knockdown; MTT assay; flow cytometry; wound scratch and transwell assays; Western blot\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with multiple orthogonal phenotypic readouts and pathway markers, single lab\",\n      \"pmids\": [\"27774979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-27b directly regulates HMGB3 expression by binding its 3'UTR; re-expression of miR-27b in tamoxifen-resistant MCF-7 cells reduces HMGB3 protein, sensitizes cells to tamoxifen, and inhibits invasion and EMT-like properties; silencing HMGB3 alone partially phenocopies these effects.\",\n      \"method\": \"Dual luciferase assay; Western blot; MSP assay; qRT-PCR; functional cell assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated direct miRNA-3'UTR binding plus functional rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27363334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HMGB3 promotes proliferation and migration in colorectal cancer by activating the WNT/β-catenin pathway, increasing downstream c-Myc and MMP7 expression.\",\n      \"method\": \"siRNA knockdown; overexpression; in vitro proliferation and migration assays; Western blot for β-catenin, c-Myc, MMP7\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with pathway protein readouts, single lab, multiple methods\",\n      \"pmids\": [\"28678825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-205-5p directly regulates HMGB3 in prostate cancer cells as confirmed by luciferase reporter assay; knockdown of HMGB3 by siRNA reduces prostate cancer cell aggressiveness.\",\n      \"method\": \"Luciferase reporter assay; siRNA knockdown; functional cell assays\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated direct miRNA-target relationship with functional KD, single lab\",\n      \"pmids\": [\"29196733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hmgb3 promotes uterine stromal cell differentiation (decidualization) by upregulating pleiotrophin (Ptn); silencing Ptn blocks Hmgb3-induced Prl8a2 expression while Ptn overexpression rescues Hmgb3 siRNA-mediated repression of Prl8a2.\",\n      \"method\": \"In situ hybridization; siRNA knockdown; overexpression; qRT-PCR; rescue experiments in mouse uterine stromal cells\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiment placing Hmgb3 upstream of Ptn in stromal cell differentiation, single lab\",\n      \"pmids\": [\"30081728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-200b-3p and miR-200c-3p directly bind the 3'UTR of HMGB3 and inhibit its expression in glioblastoma cells; HMGB3 knockdown reduces MAPK phosphorylation (ERK1/2, p38, JNK), implicating HMGB3 as an activator of the MAPK signaling pathway.\",\n      \"method\": \"Luciferase reporter assay; qRT-PCR; Western blot; siRNA knockdown; MTT and sphere assays; wound healing and transwell assays\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miRNA-target binding plus downstream MAPK pathway readout via Western blot, single lab\",\n      \"pmids\": [\"30232806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HMGB3 interacts with HIF1α; HMGB3 silencing reduces HIF1α-driven mammosphere formation, cancer stem cell markers (Nanog, SOX2, OCT-4), and CD44+/CD24− levels in breast cancer cells, as validated by dual luciferase assay.\",\n      \"method\": \"Dual luciferase assay; CCK-8 assay; mammosphere assay; flow cytometry; xenograft mouse model; qRT-PCR and Western blot\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction validated by luciferase assay with multiple functional readouts including in vivo model, single lab\",\n      \"pmids\": [\"31213919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-532-5p directly targets the 3'UTR of HMGB3 and negatively regulates its expression; HMGB3 mediates Wnt/β-catenin pathway activation, and restoration of HMGB3 partially reverses the anti-tumor effects of miR-532-5p overexpression in bladder cancer cells.\",\n      \"method\": \"Dual luciferase reporter assay; Western blot; functional cell assays; rescue experiments\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated direct miRNA-3'UTR binding with pathway and functional rescue, single lab\",\n      \"pmids\": [\"30639441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HMGB3 directly binds the hTERT promoter region (−902 to −321) and transcriptionally upregulates hTERT, thereby promoting radioresistance; HMGB3 knockdown inhibits DNA damage repair and increases γH2AX foci, while HMGB3 knockdown-mediated radiosensitization is reversed by hTERT overexpression.\",\n      \"method\": \"Streptavidin-agarose pulldown; LC/MS; luciferase reporter assay; γH2AX foci analysis; rescue assays; xenograft mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct promoter binding confirmed by streptavidin pulldown + MS + luciferase, epistasis via rescue, in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33187536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HMGB3 promotes NSCLC proliferation and invasion by activating the ERK/MAPK signaling pathway; HMGB3 overexpression increases p-ERK1/2 levels and its effects are reversed by the ERK/MAPK inhibitor PD98059.\",\n      \"method\": \"Luciferase reporter assay; Western blot for ERK/MAPK phosphorylation; ERK inhibitor rescue; in vitro proliferation/invasion assays\",\n      \"journal\": \"International journal of general medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway activation confirmed by phospho-Western and inhibitor rescue, single lab\",\n      \"pmids\": [\"33328759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LncRNA PITPNA-AS1 stabilizes HMGB3 mRNA by recruiting RNA-binding protein TAF15 in the cytosol of LUSC cells; PITPNA-AS1 depletion reduces HMGB3 mRNA stability and suppresses LUSC cell proliferation and migration.\",\n      \"method\": \"RNA immunoprecipitation; mRNA stability assay; subcellular fractionation; rescue experiments; functional cell assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-confirmed TAF15-HMGB3 mRNA interaction with mRNA stability readout, single lab\",\n      \"pmids\": [\"32871048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HMGB3 silencing inhibits NSCLC cell growth and invasion partly by inhibiting β-catenin, MMP7, and c-Myc expression in the Wnt pathway.\",\n      \"method\": \"siRNA knockdown; in vitro growth and invasion assays; Western blot for Wnt pathway proteins; xenograft model\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway protein readouts and in vivo confirmation, single lab\",\n      \"pmids\": [\"32386184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HMGB3 functions as an RNA-binding protein that binds to the TIM-TAM sequence-structure in HIV-1 tat mRNA; HMGB3 knockdown increases Tat transactivation and translation as well as productive HIV-1 infection, whereas overexpression has the opposite effect.\",\n      \"method\": \"Affinity purification coupled with mass spectrometry; luciferase-based reporter assays; RNA footprinting; dual-color HIV reporter virus infection; knockdown and overexpression\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — AP-MS identification plus luciferase reporter and footprinting confirming direct mRNA binding and functional consequence, single lab\",\n      \"pmids\": [\"34194479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HMGB3-containing nuclear exosomes (nEXOs) derived from micronuclei of NPC cells are ingested by HUVECs and accelerate angiogenesis in vitro and in vivo in a zebrafish xenograft model; HMGB3 secretion is associated with micronuclei formation.\",\n      \"method\": \"Western blot; flow cytometry; HUVEC tube formation assay; zebrafish angiogenesis xenograft model; nEXO isolation and characterization\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined exosomal secretion mechanism with in vitro and in vivo angiogenesis functional assays, single lab\",\n      \"pmids\": [\"34050127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HMGB3 inhibition by miR-142-3p or shRNA induces apoptosis in breast cancer cells via increased ROS accumulation, decreased mitochondrial membrane potential (MMP), disruption of autophagy (altered LC3, cleaved PARP, Bcl-xL), and reduced phospho-mTOR and STAT3.\",\n      \"method\": \"3'UTR luciferase reporter assay; ROS detection (DHE dye); MitoTracker for MMP; Western blot for autophagy and apoptosis markers; zebrafish xenograft for in vivo metastasis\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miRNA-target binding with multiple orthogonal mechanistic readouts, single lab\",\n      \"pmids\": [\"35753437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HMGB3 directly interacts with PARP1; this interaction is enhanced under DNA damage conditions and blocked by olaparib. HMGB3 loss causes PARP1 trapping at DNA lesions and inhibits PARylation activity of PARP1, resulting in increased DNA damage response and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation; Western blot; functional assays in olaparib-resistant/sensitive cells; xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP confirming direct HMGB3-PARP1 interaction with defined mechanistic consequence (PARP1 trapping, reduced PARylation), supported by in vivo xenograft, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35332131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SOX9 activates NANOG gene transcription by binding a conserved cis-regulatory element (−573 to −568) in the NANOG promoter; HMGB3 acts as a co-activator partner of SOX9 for this transactivation, interacting with SOX9 predominantly via the HMG Box A domain of HMGB3.\",\n      \"method\": \"Reporter gene transcription assays; protein-binding assays (Co-IP); ChIP for SOX9 binding sites; siRNA/overexpression of SOX9 and HMGB3\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms SOX9-HMGB3 interaction; luciferase reporter and domain mapping define functional interface, single lab\",\n      \"pmids\": [\"36541373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SYT7 interacts with BRCA1 to inhibit HMGB3 ubiquitination, thereby stabilizing HMGB3 protein levels in thyroid cancer cells; HMGB3 knockdown reverses the pro-tumorigenic effects of SYT7 overexpression.\",\n      \"method\": \"Co-IP assay; GeneChip transcriptomics; UbiBrowser database prediction; functional cell assays; rescue experiments\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms SYT7-BRCA1-HMGB3 interaction and ubiquitination regulation, single lab\",\n      \"pmids\": [\"35073278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC3 promotes HMGB3 expression in breast cancer by epigenetically repressing miR-130a-3p, which directly targets HMGB3; this axis facilitates immune escape by suppressing CD8+/CD69+/PD-1+ T cell cytotoxicity against cancer cells.\",\n      \"method\": \"qRT-PCR; Western blot; correlation analysis; functional cell viability, migration, EMT, and apoptosis assays; CD8+ T cell co-culture cytotoxicity assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined HDAC3→miR-130a-3p→HMGB3 regulatory axis with functional immune readout, single lab\",\n      \"pmids\": [\"33727043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HMGB3 promotes ovarian cancer stemness, proliferation, and metastasis through activation of the MAPK/ERK signaling pathway, as established by RNA-seq identifying HMGB3-regulated pathways and Western blot confirmation; these effects were also verified in a xenograft model.\",\n      \"method\": \"RNA sequencing; Western blot for MAPK/ERK pathway proteins; MTT, clonogenic, EdU, and Transwell assays; xenograft mouse model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq pathway identification with Western blot confirmation and in vivo validation, single lab\",\n      \"pmids\": [\"37328851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMGB3 directly binds N2-nBu-dG-containing duplex DNA (minor-groove alkylguanine lesion) in vitro and promotes repair of this lesion in human cells; HMGB3 shows stereospecific binding, favoring trans-N2-BPDE-dG over cis-N2-BPDE-dG; genetic ablation of HMGB3 reduces repair of trans-N2-BPDE-dG but not cis-N2-BPDE-dG.\",\n      \"method\": \"Photo-cross-linking coupled with quantitative mass spectrometry proteomics; in vitro direct DNA-binding assay; HMGB3 knockout cell lines; DNA repair assays; cell viability assay with BPDE treatment\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted binding confirmed by photo-crosslinking MS, stereospecific mechanistic distinction with KO repair assays; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39101269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exosomal HMGB3 from silica-exposed macrophages activates STAT3/MAPK(ERK1/2 and p38)/NF-κB signaling pathways in recipient monocytes/macrophages and promotes their migration via CCR2, driving M1 macrophage polarization and pulmonary inflammation.\",\n      \"method\": \"Immunofluorescence; flow cytometry; transwell migration assay; RT-PCR; ELISA; Western blot for pathway activation\",\n      \"journal\": \"Particle and fibre toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exosomal transfer mechanism with pathway activation Western blots and functional migration assay, single lab\",\n      \"pmids\": [\"38454505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cytoplasmic HMGB3 (following hypoxia-induced translocation from nucleus) activates TLR3/NF-κB signaling; extracellular HMGB3 interacts with transmembrane TREM1 receptor in papillary thyroid cancer cells, promoting cancer progression.\",\n      \"method\": \"Immunofluorescence for subcellular localization; co-immunoprecipitation; dual-luciferase reporter assay; Western blot; flow cytometry; IPA pathway analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms HMGB3-TREM1 interaction; luciferase confirms TLR3/NF-κB activation; localization by IF; single lab\",\n      \"pmids\": [\"38197217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELAVL1 (HuR) directly interacts with HMGB3 mRNA and increases its stability; HMGB3 overexpression activates β-catenin signaling and promotes glycolysis in nasopharyngeal carcinoma cells; β-catenin inhibitor FH535 suppresses HMGB3-driven glycolysis.\",\n      \"method\": \"RNA pulldown assay; RIP assay; TOPFlash/FOPFlash reporter assay; ECAR measurement; glucose/lactate assay kits; Western blot; xenograft model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and RNA pulldown confirm direct ELAVL1-HMGB3 mRNA interaction; functional glycolysis and β-catenin pathway readouts; single lab\",\n      \"pmids\": [\"39390359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMGB3 contributes to anti-PD-1 resistance in TNBC by inhibiting IFN-γ-driven ferroptosis; HMGB3 overexpression inhibits STAT1 phosphorylation and IRF1 expression upon IFN-γ treatment while activating STAT3, and increases ferroptosis-inhibitory proteins SLC7A11, GPX4, and SLC3A2.\",\n      \"method\": \"siRNA knockdown; lentiviral overexpression; Western blot for STAT1/STAT3/IRF1/ferroptosis proteins; co-IP for STAT1-STAT3 interaction; in vivo anti-PD-1 treatment mouse models; immunohistochemistry\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mechanism (HMGB3 suppresses IFN-γ/STAT1 axis, activates STAT3, upregulates ferroptosis inhibitors) with Co-IP and in vivo validation; single lab\",\n      \"pmids\": [\"39660968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMGB3 is involved in processing DNA interstrand crosslinks (ICLs) and DNA double-strand breaks (DSBs) in human cells; unlike HMGB1, HMGB3 does not play a role in nucleotide excision repair (NER).\",\n      \"method\": \"HMGB3 knockout human cell lines; UV damage/NER assay; mutagenesis assays; metaphase spreads; DNA repair foci formation assays; TagSeq analysis\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — clean KO cell lines with multiple orthogonal repair assays distinguishing ICL, DSB, and NER roles; single lab\",\n      \"pmids\": [\"41009989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HMGB3 recruits SSBP1 and induces its nuclear translocation, reprogramming mitochondrial metabolism; this elevates cytoplasmic ROS and activates PI3K/Akt signaling by downregulating PTEN, promoting LUAD cell proliferation, migration, invasion, EMT, and brain metastasis.\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry; Western blot; gain/loss-of-function; in vivo brain metastasis mouse model; scRNA-seq and bulk RNA-seq; immunohistochemistry\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifies SSBP1 as interaction partner; mechanistic epistasis (HMGB3→SSBP1 nuclear translocation→mitochondrial remodeling→ROS→PTEN down→PI3K/Akt) confirmed by multiple methods; single lab\",\n      \"pmids\": [\"41194553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGIF2 transcriptionally upregulates HMGB3 in esophageal squamous cell carcinoma; HMGB3 activates TGF-β signaling by interacting with and regulating TLR3, promoting ESCC proliferation and metastasis.\",\n      \"method\": \"Luciferase reporter assay; chromatin immunoprecipitation; co-immunoprecipitation; RNA sequencing; Western blot; in vitro and in vivo functional assays\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms TGIF2 binding to HMGB3 promoter; Co-IP confirms HMGB3-TLR3 interaction; RNA-seq identifies downstream pathway; single lab\",\n      \"pmids\": [\"41716633\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HMGB3 is a sequence-independent, chromatin-associated HMG-box protein that preferentially binds DNA regions of reduced stability and minor-groove alkyl-guanine lesions (facilitating their stereospecific repair via ICL and DSB pathways but not NER), acts as a transcriptional co-activator (e.g., cooperating with SOX9 to transactivate NANOG, and directly binding the hTERT promoter), interacts with PARP1 to modulate PARylation and DNA damage responses, binds the RNA-binding protein ELAVL1 and tat mRNA to regulate translation, recruits SSBP1 to reprogram mitochondrial metabolism, and in hematopoietic stem cells negatively regulates canonical Wnt/Dvl1 signaling to balance self-renewal versus differentiation; its overexpression in cancers promotes proliferation, invasion, radioresistance, and immunotherapy resistance through activation of Wnt/β-catenin, MAPK/ERK, and IFN-γ/STAT signaling axes, while being post-translationally regulated by SYT7/BRCA1-mediated ubiquitination and post-transcriptionally regulated by multiple miRNAs targeting its 3'UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HMGB3 is an embryonically-enriched, X-linked HMG-box chromatin protein that binds DNA in a sequence-independent but structure-selective manner, favoring regions of reduced thermodynamic stability and (A+T)-rich tracts [#0, #1]. In hematopoiesis it restrains lineage commitment: enforced expression blocks B-cell and myeloid differentiation, while its loss reduces lymphoid and myeloid progenitor output and derepresses canonical Wnt signaling through elevated Dvl1, marking HMGB3 as a negative regulator of Wnt-driven HSC self-renewal versus differentiation [#2, #3, #4]. At chromatin and DNA-damage sites HMGB3 binds minor-groove alkyl-guanine lesions stereospecifically and promotes their repair, and it participates in interstrand-crosslink and double-strand-break processing without contributing to nucleotide excision repair [#27, #32]; it directly interacts with PARP1, sustaining PARylation and preventing PARP1 trapping at lesions [#22]. HMGB3 also acts as a transcriptional co-activator, partnering with SOX9 via its HMG Box A domain to transactivate NANOG and binding the hTERT promoter to drive telomerase expression and radioresistance [#23, #15]. Beyond the nucleus it functions as an RNA-binding protein that engages a structured element of HIV-1 tat mRNA to repress Tat translation [#19], and its own mRNA is stabilized by ELAVL1/HuR and by lncRNA PITPNA-AS1/TAF15 [#30, #17]. In cancers HMGB3 is broadly overexpressed and promotes proliferation, invasion, stemness, and metabolic reprogramming through Wnt/\\u03b2-catenin, MAPK/ERK, and PI3K/Akt axes and by recruiting SSBP1 to remodel mitochondrial metabolism [#9, #26, #33], and it drives immune escape and anti-PD-1 resistance by suppressing the IFN-\\u03b3/STAT1 axis while activating STAT3 [#25, #31]. Its abundance is governed post-transcriptionally by numerous 3'UTR-targeting miRNAs and post-translationally by SYT7/BRCA1-modulated ubiquitination [#6, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established the biochemical nature of HMGB3 DNA binding, defining it as a structure-selective rather than sequence-specific reader of the genome.\",\n      \"evidence\": \"Nitrocellulose filter binding assays with immunopurified protein and synthetic polynucleotides\",\n      \"pmids\": [\"3003066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the protein-DNA complex\", \"Binding tested in vitro only, not on chromatin in cells\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined HMGB3 molecularly as an HMG1/2-family nuclear protein with embryo-restricted expression and an Xq28 location, setting its developmental context.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and chromosomal mapping\",\n      \"pmids\": [\"9598312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression pattern not linked to a function\", \"Adult tissue roles undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved HMGB3's role in hematopoiesis, showing it balances stem-cell self-renewal against differentiation by restraining canonical Wnt signaling.\",\n      \"evidence\": \"Retroviral overexpression, knockout mice, BrdU/flow cytometry, Wnt pathway analysis, and 5-FU recovery assays\",\n      \"pmids\": [\"12714519\", \"15358624\", \"16945912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking HMGB3 to Dvl1 levels unresolved\", \"Direct chromatin targets in HSCs not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended HMGB3 transcriptional control to other differentiation programs, placing it upstream of pleiotrophin in uterine decidualization.\",\n      \"evidence\": \"siRNA/overexpression rescue experiments in mouse uterine stromal cells\",\n      \"pmids\": [\"30081728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HMGB3 binds the Ptn locus directly is untested\", \"Generalizability beyond uterine stroma unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined direct transcriptional targets, showing HMGB3 binds the hTERT promoter to drive telomerase and radioresistance.\",\n      \"evidence\": \"Streptavidin pulldown + LC/MS, luciferase reporter, \\u03b3H2AX foci, and hTERT rescue in xenografts\",\n      \"pmids\": [\"33187536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-factors at the hTERT promoter not defined\", \"Relationship to its structure-selective binding unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an RNA-binding function, identifying HMGB3 as a repressor of HIV-1 Tat translation via a structured tat mRNA element.\",\n      \"evidence\": \"AP-MS, RNA footprinting, luciferase reporters, and HIV reporter-virus infection with knockdown/overexpression\",\n      \"pmids\": [\"34194479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mRNA targets of this RNA-binding activity not catalogued\", \"Domain mediating RNA binding not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected HMGB3 to the PARP1-dependent DNA damage response, showing it sustains PARylation and prevents PARP1 trapping.\",\n      \"evidence\": \"Reciprocal Co-IP, olaparib sensitivity assays, and xenografts\",\n      \"pmids\": [\"35332131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HMGB3 is a PARylation substrate or regulator is not distinguished\", \"Recruitment kinetics to lesions undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a transcriptional co-activator partnership, mapping the SOX9-HMGB3 interface to HMG Box A in NANOG activation.\",\n      \"evidence\": \"Co-IP, ChIP, domain-mapping, and luciferase reporter assays\",\n      \"pmids\": [\"36541373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the SOX9-HMGB3 interface not solved\", \"Genome-wide co-occupancy not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a direct DNA-repair function with chemical precision, showing HMGB3 binds and promotes stereospecific repair of minor-groove alkylguanine lesions.\",\n      \"evidence\": \"Photo-cross-linking quantitative MS, in vitro binding, and repair assays in HMGB3-knockout cells\",\n      \"pmids\": [\"39101269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream repair factors recruited by HMGB3 not identified\", \"Structural basis of stereoselectivity unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded HMGB3 into extracellular and signaling roles, showing secreted/translocated HMGB3 engages TLR3, TREM1, and STAT/MAPK/NF-\\u03baB cascades and drives immune escape and inflammation.\",\n      \"evidence\": \"Co-IP, luciferase reporters, exosome transfer assays, IFN-\\u03b3/anti-PD-1 mouse models, and pathway Western blots\",\n      \"pmids\": [\"33727043\", \"38454505\", \"38197217\", \"39660968\", \"39390359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-binding determinants of extracellular HMGB3 not mapped\", \"How a nuclear HMG protein reaches the cell surface mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Delineated HMGB3's lesion-specific repair pathway membership and a mitochondrial metabolic reprogramming function via SSBP1.\",\n      \"evidence\": \"Knockout cell repair assays (ICL/DSB/NER discrimination), Co-IP/MS, and in vivo metastasis models\",\n      \"pmids\": [\"41009989\", \"41194553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between SSBP1 nuclear translocation and mitochondrial remodeling incompletely defined\", \"How HMGB3 selects ICL/DSB over NER pathways unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HMGB3's distinct activities — structure-selective DNA binding, lesion repair, transcriptional co-activation, and RNA binding — are coordinated by a single protein, and what governs its subcellular partitioning between nucleus, cytoplasm, and extracellular space, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or domain-level model connecting DNA-, RNA-, and protein-binding activities\", \"Triggers and machinery for nuclear-to-extracellular relocalization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 27, 32]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [27, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 15, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [29, 17]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [20, 28, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22, 27, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9, 26, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25, 28, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"SOX9\", \"ELAVL1\", \"SSBP1\", \"TLR3\", \"TREM1\", \"HIF1A\", \"TAF15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}