{"gene":"SLC7A11","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2025,"finding":"SLC7A11 mediates a slow lysosomal H+ leak by downward flux of cystine and glutamate (two H+ equivalents with large but opposite concentration gradients across lysosomal membranes). SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, ferroptosis, and facilitated α-synuclein aggregation in neurons; correction of abnormal lysosomal acidity restored lysosome homeostasis.","method":"Candidate screen on orphan lysosome membrane protein library, genetic KO/inhibition of SLC7A11, lysosomal pH measurements, organelle fractionation, live imaging, neuronal models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (screen, KO, functional rescue, pH correction) in a single rigorous study revealing a previously unknown transport mechanism","pmids":["40280132"],"is_preprint":false},{"year":2011,"finding":"SLC7A11/xCT forms the light-chain subunit of system xc-, linked by a disulfide bridge to the heavy chain 4F2hc (SLC3A2), and mediates 1:1 exchange of extracellular cystine for intracellular glutamate; intracellularly, cystine is reduced to cysteine, the rate-limiting precursor of glutathione. Regulation extends to membrane trafficking and modulation by extracellular glutamate transport.","method":"Review of functional transport assays, disulfide-linkage biochemistry, pharmacological inhibition, and neuronal cell-line studies summarized","journal":"Amino acids","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution and transport assays replicated across multiple labs and systems; canonical mechanism well-established","pmids":["21369940"],"is_preprint":false},{"year":2019,"finding":"IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently yet synergistically suppress SLC7A11 transcription, reducing cystine uptake and enhancing tumor-cell lipid oxidation and ferroptosis.","method":"In vivo tumor models, genetic/pharmacological ferroptosis modulation, IFNγ neutralization, ATM inhibition, gene expression analysis","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo and in vitro models with mechanistic pathway validation, replicated across conditions","pmids":["31554642"],"is_preprint":false},{"year":2019,"finding":"Tumor suppressor BAP1, a H2A deubiquitinase, represses SLC7A11 expression by reducing H2A ubiquitination (H2Aub) on the SLC7A11 promoter; BAP1 inactivation leads to SLC7A11 de-repression and ferroptosis resistance. PRC1 (major H2Aub ligase) also represses SLC7A11, indicating dynamic H2Aub regulation is required for repression. BAP1-mediated ferroptosis induction is through SLC7A11 (class I FIN erastin) but not class II FIN RSL3.","method":"ChIP for H2Aub at SLC7A11 promoter, BAP1 KO/KD, PRC1 manipulation, ferroptosis assays with class I and II FINs","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, reciprocal genetic manipulation, and functional ferroptosis assays in same study","pmids":["30907299"],"is_preprint":false},{"year":2021,"finding":"SOCS2 directly binds the N-terminal domain of SLC7A11 via its SH2 domain, and uses its SOCS-BOX (L162, C166) to recruit an elongin B/C complex; this SOCS2/elongin B/C complex transfers ubiquitin to SLC7A11, promoting K48-linked polyubiquitination degradation of SLC7A11 and triggering ferroptosis.","method":"Co-IP, domain mapping, ubiquitination assays, in vivo xenograft radiosensitivity models, ferroptosis markers (lipid peroxidation, Fe2+)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, ubiquitination assay, in vivo validation; single lab with multiple orthogonal methods","pmids":["35995846"],"is_preprint":false},{"year":2021,"finding":"RNA-binding protein RBMS1 directly interacts with translation initiation factor eIF3d and bridges the 3'- and 5'-UTR of SLC7A11 mRNA to enhance its translation; RBMS1 ablation inhibits SLC7A11 translation, reducing cystine uptake and promoting ferroptosis.","method":"shRNA screen, RIP, translation assay, eIF3d pulldown, cystine uptake assay, in vivo lung cancer models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic screen plus multiple orthogonal mechanistic methods (RIP, pulldown, functional rescue) with in vivo validation","pmids":["34609966"],"is_preprint":false},{"year":2021,"finding":"UFM1-mediated UFMylation of SLC7A11 promotes its protein stability; metformin inhibits this UFMylation, thereby reducing SLC7A11 protein levels, increasing intracellular Fe2+ and lipid ROS, and inducing ferroptosis in breast cancer cells.","method":"Co-IP/immunoprecipitation for UFMylation detection, SLC7A11 protein stability assays, ferroptosis markers (Fe2+, lipid ROS, GSH), in vivo nude-mouse tumor model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — UFMylation shown by IP, stability assay, functional rescue; single lab, multiple methods","pmids":["34162423"],"is_preprint":false},{"year":2023,"finding":"TRIM3 E3 ubiquitin ligase directly interacts with SLC7A11 through its NHL domain and promotes SLC7A11 K11-linked ubiquitination at K37, leading to proteasome-mediated degradation of SLC7A11 and ferroptosis induction in NSCLC.","method":"Co-IP, domain mapping (NHL domain), ubiquitination assay (K11-linkage, K37 site), proteasome inhibitor rescue, in vivo tumor xenograft","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct interaction mapped to NHL domain, specific ubiquitin linkage and lysine identified, proteasome-dependence confirmed, in vivo validation","pmids":["37978273"],"is_preprint":false},{"year":2023,"finding":"ZRANB1 functions as an E3 ubiquitin ligase (not a deubiquitinase) for SLC7A11: it ubiquitinates and represses SLC7A11, inhibiting glutathione synthesis and promoting ferroptosis. Deletion of residues 463–584 abolishes ZRANB1's E3 activity.","method":"Whole-DUB sgRNA screen, ubiquitination assay, domain deletion mutagenesis, GSH/lipid peroxidation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide screen, E3 activity confirmed by mutagenesis of catalytic domain, mechanistic pathway validated","pmids":["37831441"],"is_preprint":false},{"year":2024,"finding":"USP52/PAN2 deubiquitylase interacts with SLC7A11/xCT and cleaves K48-linked ubiquitin chains at K4 and K12 of SLC7A11, thereby enhancing its protein stability and ferroptosis resistance in bladder cancer.","method":"siRNA screen of 96 DUBs, Co-IP, ubiquitin chain linkage analysis, site-specific mutagenesis (K4, K12), GSH/lipid peroxidation assays, in vivo xenograft","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased DUB screen, specific K48-chain cleavage at defined lysines confirmed by mutagenesis, in vivo validation","pmids":["39392373"],"is_preprint":false},{"year":2024,"finding":"AMPKα1 directly phosphorylates ZDHHC8 at S299, strengthening ZDHHC8-SLC7A11 interaction; ZDHHC8 then catalyzes S-palmitoylation of SLC7A11 at Cys327, reducing its ubiquitination and stabilizing SLC7A11 protein to confer ferroptosis resistance in glioblastoma.","method":"Co-IP, phospho-site mutagenesis (S299), palmitoylation assay (acyl-RAC), Cys327 mutagenesis, ubiquitination assay, ZDHHC8 KD rescue with SLC7A11 OE","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — kinase phosphorylation of palmitoyl transferase, specific palmitoylation site (Cys327) identified, ubiquitination link established, functional rescue performed","pmids":["38211651"],"is_preprint":false},{"year":2023,"finding":"OGT O-GlcNAcylates SLC7A11 at Ser26, a modification essential for SLC7A11 cystine import activity; USP8 stabilizes OGT by inhibiting K48-linked polyubiquitination at OGT K117, and SLK-mediated S716 phosphorylation of USP8 is required for USP8-OGT interaction.","method":"Co-IP, mass spectrometry, site-specific mutagenesis (Ser26, K117, S716), OGT KO rescue assay, cystine uptake assay, GSH measurement","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific O-GlcNAcylation site identified by MS and confirmed by mutagenesis, upstream kinase-DUB-transferase chain validated","pmids":["37867237"],"is_preprint":false},{"year":2022,"finding":"Kynurenine (KYN), exported from IDO1-expressing cells, is imported by SLC7A11 into non-IDO1-expressing neighboring cells; intracellular KYN-derived metabolites suppress ferroptosis by ROS scavenging and activation of an NRF2-dependent, AHR-independent cell-protective pathway that includes SLC7A11 upregulation, propagating anti-ferroptotic signaling.","method":"Genetic KO of SLC7A11 and IDO1, metabolite supplementation, NRF2/AHR pathway analysis, ferroptosis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO experiments with metabolite rescue, pathway dissection using NRF2 vs AHR knockouts, multiple cell systems","pmids":["35245456"],"is_preprint":false},{"year":2022,"finding":"SLC7A11 acts as a molecular brake on efferocytosis in dendritic cells; pharmacological inhibition, deletion, or siRNA knockdown of Slc7a11 enhanced efferocytosis. Mechanistically, SLC7A11-deficient DCs became dependent on aerobic glycolysis using glucose from glycogen stores. In a diabetic wound-healing model, loss of SLC7A11 accelerated wound healing and reduced apoptotic cell load, linked to GDF15 release from efferocytic DCs.","method":"Pharmacological inhibition of SLC7A11, genetic KO, siRNA KD, transcriptomics of efferocytic DCs, db/db mouse wound model, metabolic flux studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological approaches, in vivo disease model validation, mechanistic metabolic link established","pmids":["35614212"],"is_preprint":false},{"year":2020,"finding":"Slc7a11 deficiency in Fth-knockout cardiomyocytes reduces glutathione levels; overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis induced by iron overload.","method":"Conditional cardiomyocyte-specific KO (MCK-Cre, Myh6-Cre), Slc7a11 overexpression, GSH measurement, lipid peroxidation assay, ferrostatin-1 rescue","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with two Cre lines, gain-of-function rescue, multiple ferroptosis markers, in vivo cardiac phenotype","pmids":["32349646"],"is_preprint":false},{"year":2023,"finding":"ATF4 directly activates SLC7A11 transcription; SLC7A11 maintains glutathione production to inhibit ferroptosis in hepatocytes. ATF4 ablation decreased SLC7A11 expression and increased ferroptosis susceptibility; ectopic SLC7A11 expression in ATF4-deficient hepatocytes and mouse livers reversed ferroptosis and hepatocarcinogenesis.","method":"Hepatocyte-specific ATF4 KO, ectopic SLC7A11 reconstitution in KO cells/mice, GSH measurement, lipid peroxidation assays, RNA-sequencing, HCC mouse models","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus single-gene rescue by SLC7A11 reconstitution, in vivo HCC models, RNA-seq pathway analysis","pmids":["36996941"],"is_preprint":false},{"year":2021,"finding":"HBx protein promotes EZH2-mediated H3K27me3 modification at the SLC7A11 promoter, suppressing SLC7A11 transcription and facilitating ferroptosis in hepatocytes; EZH2 inhibition or SLC7A11 overexpression rescued HBx-induced ferroptosis.","method":"ChIP for H3K27me3 at SLC7A11 promoter, Co-IP for HBx-EZH2 interaction, EZH2 inhibition, SLC7A11 OE rescue, ferroptosis markers (GSH, MDA, iron)","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with functional rescue, single lab","pmids":["34615538"],"is_preprint":false},{"year":2021,"finding":"KDM4A histone demethylase removes H3K9me3 from the SLC7A11 promoter, increasing SLC7A11 transcription and inhibiting ferroptosis in osteosarcoma; KDM4A knockdown reduced SLC7A11 expression and promoted ferroptosis.","method":"ChIP for H3K9me3 at SLC7A11 promoter, KDM4A KD, ferroptosis markers, in vivo metastasis model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms epigenetic mark change at SLC7A11 promoter, KD with functional ferroptosis readout, single lab","pmids":["33689883"],"is_preprint":false},{"year":2021,"finding":"SOX2 directly binds the SLC7A11 promoter to activate its transcription; mutation of the SOX2 binding site in the SLC7A11 promoter reduced SLC7A11 expression and increased ferroptosis sensitivity. Oxidation at Cys265 of SOX2 inhibited its transcriptional activity toward SLC7A11.","method":"SLC7A11 promoter-reporter assay, SOX2 binding-site mutagenesis, Cys265 mutagenesis, ferroptosis assays, lung cancer stem-like cell models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter mutagenesis, site-specific oxidation mutagenesis, functional ferroptosis validation in cancer stem cells","pmids":["34385181"],"is_preprint":false},{"year":2023,"finding":"NFATc1 transcriptionally upregulates SLC7A11 during RANKL-induced osteoclastogenesis; elevated SLC7A11 increases cystine transport leading to cystine accumulation upon TXNRD1 inhibition, causing disulfidptosis (not ferroptosis) specifically in osteoclast precursors.","method":"ChIP/transcriptional reporter for NFATc1-SLC7A11, SLC7A11 inhibitors, ferroptosis vs. disulfidptosis inhibitor panel, in vivo OVX mouse model, bone cystine measurement","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation confirmed by ChIP, mechanistic cell-death modality dissected with specific inhibitors, in vivo validation; single lab","pmids":["37148740"],"is_preprint":false},{"year":2022,"finding":"METTL3-mediated m6A modification of SLC7A11 mRNA is read by IGF2BP1, which competitively binds PABPC1 to block BTG2/CCR4-NOT complex recruitment, thereby inhibiting SLC7A11 mRNA deadenylation and enhancing mRNA stability and expression in hepatoblastoma.","method":"MeRIP-qPCR, RNA pulldown, RIP, RACE-PAT (deadenylation assay), dual luciferase reporter, m6A quantification","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal RNA biochemical methods (MeRIP, RIP, pulldown, deadenylation assay) establish mechanism in a single study","pmids":["35522946"],"is_preprint":false},{"year":2022,"finding":"PHGDH binds to RNA-binding protein PCBP2 and inhibits its ubiquitination degradation; stabilized PCBP2 in turn stabilizes SLC7A11 mRNA, increasing SLC7A11 expression and inhibiting ferroptosis in bladder cancer.","method":"Co-IP, mass spectrometry, RIP assay, ubiquitination assay, SLC7A11 mRNA stability assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and RIP with MS identification, ubiquitination assay, mRNA stability confirmed; single lab","pmids":["36147463"],"is_preprint":false},{"year":2020,"finding":"RNA-binding protein DAZAP1 interacts with the 3'UTR of SLC7A11 mRNA and positively regulates its stability, thereby inhibiting ferroptosis in HCC.","method":"RNA immunoprecipitation (RIP), 3'UTR binding assay, mRNA stability assay, ferroptosis assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and functional mRNA stability assay, single lab","pmids":["33358859"],"is_preprint":false},{"year":2022,"finding":"CEBPG directly binds the SLC7A11 promoter and transcriptionally activates SLC7A11 expression to suppress ferroptosis in ovarian cancer.","method":"CUT&Tag chromatin profiling, dual luciferase reporter assay, CEBPG KD, RNA-sequencing, ferroptosis assays, orthotopic mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag and luciferase reporter confirm direct promoter binding, functional validation with KD; single lab","pmids":["37210575"],"is_preprint":false},{"year":2021,"finding":"EZH2 promotes SLC7A11 expression by repressing miR-125b-5p (which targets SLC7A11 3'UTR), thereby inhibiting ferroptosis in tongue squamous cell carcinoma; dual-luciferase assays confirmed EZH2 binding to miR-125b-5p promoter and miR-125b-5p binding to SLC7A11 3'UTR.","method":"Dual-luciferase reporter assays, RT-qPCR, Western blot, CCK-8, MDA assay","journal":"Oral diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase reporters validate two-step regulatory axis; single lab, limited methods beyond reporter assays","pmids":["34614259"],"is_preprint":false},{"year":2022,"finding":"ALKBH5 erases m6A modification on SLC7A11 mRNA, reducing its stability and expression, thereby promoting ferroptosis in colorectal cancer cells.","method":"m6A quantitative analysis, MeRIP-qPCR, mRNA stability assay (actinomycin D), ALKBH5 OE and SLC7A11 OE rescue, in vivo xenograft","journal":"Clinical & translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and mRNA stability assay confirm m6A-dependent regulation; single lab, in vivo validation","pmids":["36820954"],"is_preprint":false},{"year":2024,"finding":"FTO m6A demethylase increases SLC7A11 expression in an m6A-YTHDF2-dependent manner; high FTO stabilizes SLC7A11 mRNA, counteracting ferroptosis in colorectal cancer.","method":"m6A modification analysis, YTHDF2 interaction studies, SLC7A11 mRNA stability assay, FTO KD/OE, in vivo CRC models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A reader/writer mechanism with mRNA stability assay; single lab","pmids":["38600610"],"is_preprint":false},{"year":2023,"finding":"STAT6 competes with the acetyltransferase CBP to inhibit p53 acetylation, thereby transcriptionally restoring SLC7A11 expression and suppressing ferroptosis in lung epithelial cells during acute lung injury.","method":"ChIP, Co-IP for STAT6-CBP interaction, p53 acetylation assay, STAT6 KD/OE, SLC7A11 promoter-reporter, lung-specific STAT6 OE in ALI mouse models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP mechanistic data, in vivo ALI validation; single lab","pmids":["35668064"],"is_preprint":false},{"year":2024,"finding":"SPTBN2 interacts with SLC7A11 through its CH domain and connects it with motor protein Arp1, facilitating SLC7A11 membrane localization—a prerequisite for its cystine-uptake/GSH-synthesis function as System Xc-; SPTBN2 inhibition reduces membrane SLC7A11 and sensitizes NSCLC to ferroptosis.","method":"Co-IP (SPTBN2-SLC7A11-Arp1), membrane fractionation, ferroptosis assays (lipid ROS, GSH), in vivo cisplatin sensitivity model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain identification, membrane fractionation functional link, in vivo validation; single lab","pmids":["38241838"],"is_preprint":false},{"year":2025,"finding":"Galectin-13 secreted from ferroptotic cells binds CD44 on neighboring cells and inhibits SLC7A11 plasma membrane localization, thereby reducing cystine uptake and propagating ferroptosis to neighboring cells. FOXK1, phosphorylated by PKCβII, drives Galectin-13 expression and secretion during ferroptosis.","method":"Galectin-13 secretion measurement, Co-IP (Galectin-13 with CD44), SLC7A11 membrane localization by fractionation/imaging, FOXK1 phosphorylation assay, functional ferroptosis propagation assays, synthetic mimetic peptide experiments","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (secretion assay, Co-IP, membrane fractionation, synthetic mimetic peptide) establish a new ferroptosis propagation mechanism","pmids":["40246981"],"is_preprint":false},{"year":2024,"finding":"NINJ1 physically interacts with the xCT antiporter (SLC7A11); NINJ1 knockdown increases xCT protein levels and stability, enhancing cystine uptake, CoA, and GSH levels, thereby protecting against ferroptosis induced by xCT inhibitors specifically.","method":"Co-IP (NINJ1-xCT), NINJ1 KD/OE, xCT protein stability assay, cystine uptake assay, compound screen (PANKi, BSO, DEM), ferroptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes physical interaction, mechanistic dissection with pharmacological probes; single lab","pmids":["39424803"],"is_preprint":false},{"year":2024,"finding":"Tumor suppressor BAP1 (H2A deubiquitinase) suppresses disulfidptosis through repression of SLC7A11: BAP1 suppresses SLC7A11 expression; SLC7A11 overexpression or additional cystine counteracts BAP1's protection against disulfidptosis; conversely, BAP1-mediated suppression of disulfidptosis is abrogated when SLC7A11-mediated cystine uptake is genetically or pharmacologically blocked.","method":"SLC7A11 KO/OE, disulfide bond accumulation assay (cytoskeleton proteins), cell death inhibitor panel, cystine supplementation, BAP1 OE","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (BAP1/SLC7A11 double manipulation), disulfidptosis-specific markers; single lab","pmids":["39266549"],"is_preprint":false},{"year":2023,"finding":"CIC (Capicua) transcriptionally represses SLC7A11/xCT expression; non-phosphorylatable CIC (S173) that cannot interact with 14-3-3 showed stronger repressor function; CIC restoration in an oligodendroglioma line reduced SLC7A11 levels and extracellular glutamate release.","method":"CIC KO/re-expression, RNA-sequencing, extracellular glutamate measurement, CIC-S173 phospho-mutant analysis, 14-3-3 interaction studies","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with RNA-seq, functional glutamate release assay, phospho-mutant mechanistic dissection; single lab","pmids":["36647117"],"is_preprint":false},{"year":2019,"finding":"CD44 variant (CD44v8-10) stabilizes xCT/SLC7A11 protein on the cell surface, promoting reduced glutathione production and antioxidant defense; during endothelial-to-mesenchymal transition (EndMT), CD44v+ cells co-express high xCT and show enhanced survival dependent on this axis.","method":"Cell-surface xCT quantification, GSH measurement, pharmacological inhibition (sulfasalazine), in vivo Sugen5416/hypoxia PAH model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional protein stabilization shown pharmacologically and in vivo, but direct CD44v-xCT interaction mechanism inferred from prior cancer work; single lab","pmids":["30897333"],"is_preprint":false},{"year":2022,"finding":"Secreted AGR2 from tumor-associated neutrophils binds CD98hc as its functional receptor and increases xCT/SLC7A11 transporter activity in a CD98hc-dependent manner, subsequently activating RhoA/ROCK2 cascade to promote CRC metastasis.","method":"Co-IP (AGR2-CD98hc), neutrophil-specific Agr2 KO mice, xCT activity assay, RhoA/ROCK2 pathway analysis, in vivo liver metastasis model","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for receptor identification, genetic KO in vivo validation, pathway analysis; single lab","pmids":["35086885"],"is_preprint":false},{"year":2023,"finding":"AhR (aryl hydrocarbon receptor) transcriptionally regulates SLC7A11 expression; pharmacological inactivation or genetic ablation of AhR suppresses SLC7A11 and enhances erastin-induced ferroptosis; the endogenous AhR ligand indole-3-pyruvate protects against ferroptosis through an AhR-SLC7A11 dependent mechanism. Post-translational modifications of SLC7A11 were also detected during ferroptosis.","method":"AhR KO/pharmacological inhibition, SLC7A11 transcription analysis, AhR ChIP (implied by transcriptional regulation), ferroptosis assays (lipid peroxidation), I3P supplementation","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological AhR manipulation with functional ferroptosis readouts; post-translational modification noted but not fully characterized; single lab","pmids":["38641223"],"is_preprint":false},{"year":2024,"finding":"PIAS4 directly binds SLC7A11 and facilitates its SUMOylation; KDM1A acts as a transcriptional activator of PIAS4; tanshinone IIA reduces KDM1A expression, thereby suppressing PIAS4 transcription, reducing SLC7A11 SUMOylation, and destabilizing SLC7A11 to promote ferroptosis in breast cancer.","method":"Ni-beads pull-down assay, Co-IP, luciferase assay, ChIP, SUMOylation assay, in vivo xenograft/lung metastasis models","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMOylation shown by pull-down and Co-IP, transcriptional axis confirmed by luciferase/ChIP; single lab","pmids":["38615741"],"is_preprint":false},{"year":2023,"finding":"Sulforaphane (SFN) directly targets p62 protein, enhancing p62-SLC7A11 protein-protein interaction, which promotes autolysosomal (lysosomal) degradation of SLC7A11 and triggers ferroptosis in osteosarcoma.","method":"p62-SLC7A11 Co-IP, lysosomal degradation inhibitor experiments, ferroptosis markers, in vivo subcutaneous and intratibial OS xenograft models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interaction, lysosomal pathway confirmed pharmacologically, in vivo validation; single lab","pmids":["39657365"],"is_preprint":false},{"year":2023,"finding":"RBM3 binds SLC7A11 mRNA; sodium butyrate promotes RBM3 expression, which indirectly downregulates SLC7A11 and promotes ferroptosis in endometrial cancer cells.","method":"RNA pulldown and mass spectrometry (RBM3-SLC7A11 mRNA), transcriptome analysis, metabolome analysis, in vivo xenograft","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown/MS identifies RBM3-SLC7A11 mRNA interaction; functional axis confirmed with NaBu treatment; single lab","pmids":["37170022"],"is_preprint":false},{"year":2023,"finding":"DUBA deubiquitinase stabilizes SLC7A11 protein in differentiated cells; elevated SLC7A11 in turn increases c-Myc expression through cysteine; undifferentiated (stem) cells express low DUBA/SLC7A11 and are more sensitive to ferroptosis.","method":"DUBA KD/OE, SLC7A11 ubiquitination assay, c-Myc expression analysis, cysteine supplementation rescue, sorafenib + c-Myc inhibitor combination assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assay, c-Myc downstream link via cysteine, functional cell-death assay; single lab","pmids":["37537342"],"is_preprint":false},{"year":2024,"finding":"FMRP promotes SLC7A11 expression via two mechanisms: (1) it catalyzes m6A modification of SLC7A11 mRNA in a METTL3-dependent manner, influencing translation; (2) FMRP interacts with splicing factor hnRNPM to modulate an exon-skip splicing event of SLC7A11 transcript, generating the SLC7A11-S variant that promotes ferroptosis resistance in breast cancer.","method":"RIP, METTL3-dependency analysis, Co-IP (FMRP-hnRNPM), splicing analysis, ferroptosis assays, clinical sample correlation","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal mechanisms (m6A and splicing) supported by RIP and Co-IP; single lab","pmids":["39388855"],"is_preprint":false},{"year":2025,"finding":"METTL3 methylates adenine +1795 on SLC7A11 mRNA; the m6A reader IGF2BP2 recognizes this site and promotes SLC7A11 mRNA stability. Separately, METTL3 decreases SLC7A11 protein ubiquitination through the m6A/YTHDF2/SOCS2 axis. Both mechanisms require METTL3 methyltransferase activity.","method":"m6A site mapping (adenine +1795), RIP for IGF2BP2-SLC7A11 mRNA, mRNA stability assay, ubiquitination assay, SOCS2-YTHDF2 pathway analysis, in vivo HCC radiosensitivity models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific m6A site identified, two mechanistic branches (mRNA stability and protein ubiquitination) mapped; single lab","pmids":["39799112"],"is_preprint":false}],"current_model":"SLC7A11/xCT is the light-chain subunit of the plasma-membrane system xc- antiporter (paired with SLC3A2/4F2hc via a disulfide bond) that exchanges extracellular cystine for intracellular glutamate 1:1, providing cysteine for glutathione biosynthesis and antioxidant defense; it additionally localizes to lysosomes where it mediates a slow H+ leak through downward flux of cystine and glutamate, regulating lysosomal pH and degradative capacity. SLC7A11 protein stability is dynamically controlled by a network of post-translational modifications—including K48-linked polyubiquitination (by E3 ligases SOCS2, TRIM3, ZRANB1) that targets it for proteasomal degradation, deubiquitination (by USP52, DUBA) that stabilizes it, S-palmitoylation at Cys327 (by ZDHHC8, itself activated by AMPKα1 phosphorylation) that protects against ubiquitination, O-GlcNAcylation at Ser26 (by OGT, stabilized by USP8) that is essential for cystine import activity, and SUMOylation (by PIAS4) that promotes stability—as well as by lysosomal degradation through a p62-SLC7A11 interaction and by membrane trafficking regulated by SPTBN2-Arp1. Its transcription is activated by ATF4, NRF2, SOX2, CEBPG, NFATc1, STAT6 (via p53 acetylation suppression), AhR, and STAT1, and repressed by BAP1-mediated H2A deubiquitination, EZH2/H3K27me3, KDM4A-reversed H3K9me3, p53, ATF3, and CIC; SLC7A11 mRNA stability and translation are regulated by multiple RNA-binding proteins (RBMS1 via eIF3d bridging of 5'/3'-UTRs, DAZAP1, RBM3, FMRP/hnRNPM) and m6A modifications (METTL3/IGF2BP1/2, FTO/YTHDF2, ALKBH5). Physiologically, high SLC7A11 suppresses ferroptosis by maintaining GSH, imports kynurenine to propagate anti-ferroptotic NRF2 signaling, acts as a brake on efferocytosis in dendritic cells (shifting metabolism toward glycolysis), and regulates extracellular glutamate in the CNS; ferroptotic cells can propagate cell death to neighbors by secreting Galectin-13, which inhibits SLC7A11 membrane localization via CD44 binding."},"narrative":{"mechanistic_narrative":"SLC7A11 (xCT) is the substrate-specific light-chain subunit of the plasma-membrane cystine/glutamate antiporter system xc-, disulfide-linked to the heavy chain 4F2hc/SLC3A2, exchanging extracellular cystine for intracellular glutamate to supply cysteine for glutathione synthesis and antioxidant defense [PMID:21369940]. Through this function it is the central cellular determinant of ferroptosis sensitivity: high SLC7A11 maintains GSH and suppresses lipid peroxidation, while its loss or inhibition triggers ferroptotic death across diverse tissues including cardiomyocytes, hepatocytes, and tumors [PMID:32349646, PMID:36996941]. Beyond the cell surface, SLC7A11 also resides on lysosomes where downward flux of cystine and glutamate mediates a slow H+ leak that regulates lysosomal pH and degradative capacity; its deficiency causes over-acidification, impaired degradation, and facilitates α-synuclein aggregation in neurons [PMID:40280132]. SLC7A11 abundance and activity are governed by an exceptionally dense post-translational network: K48/K11-linked polyubiquitination by E3 ligases SOCS2, TRIM3, and ZRANB1 drives proteasomal degradation [PMID:35995846, PMID:37978273, PMID:37831441], while deubiquitinases USP52 and DUBA, S-palmitoylation at Cys327 by AMPKα1-activated ZDHHC8, O-GlcNAcylation at Ser26 by OGT (essential for cystine import), and PIAS4-mediated SUMOylation stabilize the protein or its transport function [PMID:39392373, PMID:38211651, PMID:37867237, PMID:38615741, PMID:37537342]. Membrane delivery requires SPTBN2-Arp1 trafficking, and surface localization is antagonized by secreted Galectin-13 acting through CD44 to propagate ferroptosis to neighboring cells [PMID:38241838, PMID:40246981]. Transcriptionally, SLC7A11 is activated by ATF4, SOX2, CEBPG, NFATc1, STAT6, and AhR and repressed by the BAP1/PRC1 H2A-ubiquitination axis, EZH2/H3K27me3, and CIC [PMID:36996941, PMID:34385181, PMID:37210575, PMID:30907299, PMID:34615538, PMID:36647117], and its mRNA is further tuned by RNA-binding proteins (RBMS1, DAZAP1) and m6A machinery (METTL3/IGF2BP1/2, FTO/YTHDF2, ALKBH5) [PMID:34609966, PMID:35522946, PMID:36820954, PMID:39799112]. Functionally, SLC7A11 imports kynurenine to propagate anti-ferroptotic NRF2 signaling, acts as a metabolic brake on dendritic-cell efferocytosis, and regulates CNS extracellular glutamate; excessive cystine uptake under thioredoxin-reductase inhibition can instead drive disulfidptosis [PMID:35245456, PMID:35614212, PMID:37148740, PMID:36647117].","teleology":[{"year":2011,"claim":"Established the core biochemical identity of SLC7A11 as the cystine/glutamate antiporter light chain, defining how it supplies the rate-limiting precursor for glutathione synthesis.","evidence":"Synthesis of transport assays, disulfide-linkage biochemistry, and pharmacological inhibition in neuronal systems","pmids":["21369940"],"confidence":"High","gaps":["Did not resolve the transporter's role in regulated cell death","Structural basis of cystine/glutamate exchange not addressed"]},{"year":2019,"claim":"Connected SLC7A11 transcriptional suppression to immunotherapy and radiotherapy efficacy, establishing it as a therapeutically targetable node controlling tumor ferroptosis.","evidence":"In vivo tumor models with IFNγ neutralization, ATM inhibition, and ferroptosis modulation","pmids":["31554642"],"confidence":"High","gaps":["Direct transcription factors downstream of IFNγ/ATM at the SLC7A11 promoter not fully mapped"]},{"year":2019,"claim":"Defined epigenetic and surface-protein control of SLC7A11, showing BAP1-mediated H2A deubiquitination represses transcription while CD44v8-10 stabilizes surface protein to govern antioxidant defense.","evidence":"ChIP for H2Aub, BAP1/PRC1 genetic manipulation, ferroptosis assays; cell-surface xCT quantification and GSH measurement in EndMT/PAH models","pmids":["30907299","30897333"],"confidence":"High","gaps":["Direct physical CD44v-xCT interaction inferred rather than mapped in [#33]","How dynamic H2Aub balance is set at the promoter not resolved"]},{"year":2020,"claim":"Demonstrated in vivo that SLC7A11 sustains GSH to prevent iron-overload ferroptosis in cardiomyocytes, extending its protective role beyond cancer to organ physiology.","evidence":"Cardiomyocyte-specific conditional KO and overexpression with ferrostatin-1 rescue","pmids":["32349646"],"confidence":"High","gaps":["Upstream regulators of cardiac SLC7A11 not defined","Did not address lysosomal function"]},{"year":2020,"claim":"Opened the mRNA-stability layer of SLC7A11 regulation, showing 3'UTR-binding RBPs tune transcript abundance and thereby ferroptosis sensitivity.","evidence":"RIP, 3'UTR binding and mRNA stability assays for DAZAP1 in HCC","pmids":["33358859"],"confidence":"Medium","gaps":["Single Co-IP/RIP without reciprocal validation","Direct binding motif not mapped"]},{"year":2021,"claim":"Identified ubiquitin-dependent degradation of SLC7A11 by E3 ligase SOCS2, establishing the first substrate-receptor mechanism targeting the transporter for proteasomal turnover.","evidence":"Co-IP with domain mapping (SH2/SOCS-BOX), elongin B/C recruitment, ubiquitination assays, in vivo radiosensitivity models","pmids":["35995846"],"confidence":"High","gaps":["Counteracting deubiquitinases for SOCS2-driven chains not identified here","Physiological trigger for SOCS2 engagement unclear"]},{"year":2021,"claim":"Revealed translational control of SLC7A11, with RBMS1 bridging 5'/3'-UTRs via eIF3d to enhance translation and govern cystine uptake.","evidence":"shRNA screen, RIP, translation and eIF3d pulldown assays, cystine uptake, in vivo lung cancer models","pmids":["34609966"],"confidence":"High","gaps":["Signals controlling RBMS1 activity not defined"]},{"year":2021,"claim":"Expanded epigenetic and post-translational regulation, showing histone-modification enzymes (EZH2/H3K27me3, KDM4A/H3K9me3), SOX2 transcriptional activation, miRNA axes, and UFMylation each set SLC7A11 levels.","evidence":"ChIP for histone marks, promoter-reporter and binding-site mutagenesis, dual-luciferase miRNA assays, UFMylation IP and stability assays","pmids":["34615538","33689883","34385181","34614259","34162423"],"confidence":"Medium","gaps":["Several axes rest on single-lab reporter assays","Hierarchy among competing transcriptional inputs unresolved","UFM1 ligase machinery for SLC7A11 not identified"]},{"year":2022,"claim":"Established non-canonical signaling and immunometabolic roles: SLC7A11 imports kynurenine to propagate NRF2-dependent anti-ferroptotic signaling and acts as a metabolic brake on dendritic-cell efferocytosis.","evidence":"Genetic KO of SLC7A11/IDO1 with metabolite rescue and NRF2/AHR dissection; pharmacological/genetic SLC7A11 ablation, metabolic flux, db/db wound-healing model","pmids":["35245456","35614212"],"confidence":"High","gaps":["Structural basis for kynurenine transport by SLC7A11 not defined","Link between transporter activity and glycolytic rewiring mechanistically incomplete"]},{"year":2022,"claim":"Defined the m6A and RBP layer of mRNA stability control, with METTL3/IGF2BP1 blocking deadenylation and PCBP2 (stabilized by PHGDH) and additional factors setting transcript half-life.","evidence":"MeRIP, RIP, RNA pulldown, deadenylation (RACE-PAT) and mRNA stability assays","pmids":["35522946","36147463","35086885"],"confidence":"Medium","gaps":["Single-lab mechanisms not cross-validated","Interplay among multiple m6A writers/readers on the same transcript unresolved"]},{"year":2023,"claim":"Mapped specific ubiquitin linkages and lysine sites for SLC7A11 degradation (TRIM3 K11/K37, ZRANB1) and opposing deubiquitination/stabilization (DUBA, OGT O-GlcNAcylation at Ser26 with USP8/SLK control), defining a precise PTM grammar for transporter turnover and activity.","evidence":"Co-IP, domain mapping, linkage- and site-specific ubiquitination and O-GlcNAcylation assays, mass spectrometry, functional rescue, in vivo xenografts","pmids":["37978273","37831441","37537342","37867237"],"confidence":"High","gaps":["Cross-talk between distinct ubiquitin linkages on SLC7A11 not integrated","Physiological cues directing each ligase/DUB to the substrate unclear"]},{"year":2023,"claim":"Broadened transcriptional regulation across tissues (ATF4, CEBPG, NFATc1, STAT6, AhR, CIC) and tied SLC7A11 to distinct death modalities, including NFATc1-driven disulfidptosis in osteoclast precursors and CIC-controlled CNS glutamate release.","evidence":"Tissue-specific KO/rescue, ChIP/CUT&Tag, promoter-reporter, p53-acetylation and 14-3-3/phospho-mutant analyses, death-modality inhibitor panels, in vivo disease models","pmids":["36996941","37210575","37148740","35668064","38641223","36647117"],"confidence":"Medium","gaps":["Several transcriptional axes are single-lab","Conditions that switch SLC7A11 output between ferroptosis protection and disulfidptosis vulnerability not unified"]},{"year":2024,"claim":"Resolved palmitoylation- and SUMOylation-based stabilization (AMPKα1-ZDHHC8-Cys327; PIAS4) and deubiquitinase USP52 control, plus trafficking by SPTBN2-Arp1 as a prerequisite for surface transport activity.","evidence":"Acyl-RAC palmitoylation and SUMOylation assays, site-specific mutagenesis (Cys327), DUB siRNA screen, Co-IP/membrane fractionation, in vivo models","pmids":["38211651","38615741","39392373","38241838"],"confidence":"High","gaps":["Interplay between palmitoylation, ubiquitination, and trafficking not temporally ordered","Some interactions (SPTBN2, PIAS4) rest on single-lab Co-IP"]},{"year":2024,"claim":"Extended mRNA and protein regulation through additional m6A enzymes and RBPs (FTO/YTHDF2, FMRP/hnRNPM splicing, METTL3/IGF2BP2 and METTL3/YTHDF2/SOCS2) and identified NINJ1 as a physical interactor limiting xCT stability.","evidence":"m6A site mapping, RIP, splicing and stability assays, Co-IP, ubiquitination assays, in vivo models","pmids":["38600610","39388855","39799112","39424803"],"confidence":"Medium","gaps":["Multiple parallel m6A mechanisms not reconciled","NINJ1-xCT mechanism rests on single-lab Co-IP"]},{"year":2025,"claim":"Discovered an organelle-level function—lysosomal H+ leak via SLC7A11 controlling lysosomal pH, degradation, and neuronal α-synuclein aggregation—and a non-cell-autonomous ferroptosis propagation circuit through secreted Galectin-13/CD44 inhibition of xCT membrane localization.","evidence":"Orphan lysosomal-protein screen, KO/inhibition, lysosomal pH measurement and rescue; Galectin-13 secretion, CD44 Co-IP, membrane fractionation, FOXK1/PKCβII phosphorylation, mimetic-peptide assays","pmids":["40280132","40246981"],"confidence":"High","gaps":["Structural mechanism of lysosomal H+ leak vs plasma-membrane antiport not defined","How surface vs lysosomal pools are partitioned and regulated unknown"]},{"year":null,"claim":"How the dozens of competing transcriptional, RNA-level, and post-translational inputs are integrated to set SLC7A11 surface vs lysosomal abundance in a given cell state, and the structural basis distinguishing its antiport, kynurenine import, and lysosomal H+-leak functions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of regulatory hierarchy","No structure linking transport modes","Determinants of plasma-membrane vs lysosomal localization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,11,12,28]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,28,29,33]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,37]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3,14,15,29]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,12,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[12,35]}],"complexes":["system xc- (SLC7A11/SLC3A2 antiporter)"],"partners":["SLC3A2","SOCS2","TRIM3","ZRANB1","USP52","ZDHHC8","SPTBN2","CD44"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPY5","full_name":"Cystine/glutamate transporter","aliases":["Amino acid transport system xc-","Calcium channel blocker resistance protein CCBR1","Solute carrier family 7 member 11","xCT"],"length_aa":501,"mass_kda":55.4,"function":"Heterodimer with SLC3A2, that functions as an antiporter by mediating the exchange of extracellular anionic L-cystine and intracellular L-glutamate across the cellular plasma membrane (PubMed:11133847, PubMed:11417227, PubMed:14722095, PubMed:15151999, PubMed:34880232, PubMed:35245456, PubMed:35352032). Provides L-cystine for the maintenance of the redox balance between extracellular L-cystine and L-cysteine and for the maintenance of the intracellular levels of glutathione that is essential for cells protection from oxidative stress (By similarity). The transport is sodium-independent, electroneutral with a stoichiometry of 1:1, and is drove by the high intracellular concentration of L-glutamate and the intracellular reduction of L-cystine (PubMed:11133847, PubMed:11417227). Acts as an inhibitor of ferroptosis by mediating the import of L-kynurenine leading to anti-ferroptotic signaling propagation required to maintain L-cystine and glutathione homeostasis (PubMed:35245456, PubMed:40246981). Also inhibits ferroptosis by acting as an atypical proton transporter that mediates a slow proton efflux from lysosomes via cystine and glutamate flux (PubMed:40280132). Glutamate and cystine contain side-chain groups that are protonatable in the physiological range of lysosomal pH and cytosolic pH, respectively, enabling a slow lysosomal proton leak through a substrate-as-proton mechanism (PubMed:40280132). Moreover, mediates N-acetyl-L-cysteine uptake into the placenta leading to subsequently down-regulation of pathways associated with oxidative stress, inflammation and apoptosis (PubMed:34120018). In vitro can also transport L-aspartate (PubMed:11417227). May participate in astrocyte and meningeal cell proliferation during development and can provide neuroprotection by promoting glutathione synthesis and delivery from non-neuronal cells such as astrocytes and meningeal cells to immature neurons (By similarity). Controls the production of pheomelanin pigment directly (By similarity)","subcellular_location":"Cell membrane; Lysosome membrane; Cell projection, microvillus membrane","url":"https://www.uniprot.org/uniprotkb/Q9UPY5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC7A11","classification":"Not Classified","n_dependent_lines":29,"n_total_lines":1208,"dependency_fraction":0.024006622516556293},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC7A11","total_profiled":1310},"omim":[{"mim_id":"607933","title":"SOLUTE CARRIER FAMILY 7 (CATIONIC AMINO ACID TRANSPORTER, y+ SYSTEM), MEMBER 11; SLC7A11","url":"https://www.omim.org/entry/607933"},{"mim_id":"604735","title":"UBIQUITIN-SPECIFIC PROTEASE 16; USP16","url":"https://www.omim.org/entry/604735"},{"mim_id":"260350","title":"PANCREATIC CANCER","url":"https://www.omim.org/entry/260350"},{"mim_id":"191170","title":"TUMOR PROTEIN p53; TP53","url":"https://www.omim.org/entry/191170"},{"mim_id":"137800","title":"GLIOMA SUSCEPTIBILITY 1; GLM1","url":"https://www.omim.org/entry/137800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":12.7}],"url":"https://www.proteinatlas.org/search/SLC7A11"},"hgnc":{"alias_symbol":["xCT"],"prev_symbol":[]},"alphafold":{"accession":"Q9UPY5","domains":[{"cath_id":"1.20.1740.10","chopping":"45-495","consensus_level":"high","plddt":91.3384,"start":45,"end":495}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPY5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPY5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPY5-F1-predicted_aligned_error_v6.png","plddt_mean":85.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC7A11","jax_strain_url":"https://www.jax.org/strain/search?query=SLC7A11"},"sequence":{"accession":"Q9UPY5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPY5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPY5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPY5"}},"corpus_meta":[{"pmid":"33000412","id":"PMC_33000412","title":"Cystine 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(two H+ equivalents with large but opposite concentration gradients across lysosomal membranes). SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, ferroptosis, and facilitated α-synuclein aggregation in neurons; correction of abnormal lysosomal acidity restored lysosome homeostasis.\",\n      \"method\": \"Candidate screen on orphan lysosome membrane protein library, genetic KO/inhibition of SLC7A11, lysosomal pH measurements, organelle fractionation, live imaging, neuronal models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (screen, KO, functional rescue, pH correction) in a single rigorous study revealing a previously unknown transport mechanism\",\n      \"pmids\": [\"40280132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SLC7A11/xCT forms the light-chain subunit of system xc-, linked by a disulfide bridge to the heavy chain 4F2hc (SLC3A2), and mediates 1:1 exchange of extracellular cystine for intracellular glutamate; intracellularly, cystine is reduced to cysteine, the rate-limiting precursor of glutathione. Regulation extends to membrane trafficking and modulation by extracellular glutamate transport.\",\n      \"method\": \"Review of functional transport assays, disulfide-linkage biochemistry, pharmacological inhibition, and neuronal cell-line studies summarized\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution and transport assays replicated across multiple labs and systems; canonical mechanism well-established\",\n      \"pmids\": [\"21369940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently yet synergistically suppress SLC7A11 transcription, reducing cystine uptake and enhancing tumor-cell lipid oxidation and ferroptosis.\",\n      \"method\": \"In vivo tumor models, genetic/pharmacological ferroptosis modulation, IFNγ neutralization, ATM inhibition, gene expression analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo and in vitro models with mechanistic pathway validation, replicated across conditions\",\n      \"pmids\": [\"31554642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tumor suppressor BAP1, a H2A deubiquitinase, represses SLC7A11 expression by reducing H2A ubiquitination (H2Aub) on the SLC7A11 promoter; BAP1 inactivation leads to SLC7A11 de-repression and ferroptosis resistance. PRC1 (major H2Aub ligase) also represses SLC7A11, indicating dynamic H2Aub regulation is required for repression. BAP1-mediated ferroptosis induction is through SLC7A11 (class I FIN erastin) but not class II FIN RSL3.\",\n      \"method\": \"ChIP for H2Aub at SLC7A11 promoter, BAP1 KO/KD, PRC1 manipulation, ferroptosis assays with class I and II FINs\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, reciprocal genetic manipulation, and functional ferroptosis assays in same study\",\n      \"pmids\": [\"30907299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOCS2 directly binds the N-terminal domain of SLC7A11 via its SH2 domain, and uses its SOCS-BOX (L162, C166) to recruit an elongin B/C complex; this SOCS2/elongin B/C complex transfers ubiquitin to SLC7A11, promoting K48-linked polyubiquitination degradation of SLC7A11 and triggering ferroptosis.\",\n      \"method\": \"Co-IP, domain mapping, ubiquitination assays, in vivo xenograft radiosensitivity models, ferroptosis markers (lipid peroxidation, Fe2+)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, ubiquitination assay, in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35995846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNA-binding protein RBMS1 directly interacts with translation initiation factor eIF3d and bridges the 3'- and 5'-UTR of SLC7A11 mRNA to enhance its translation; RBMS1 ablation inhibits SLC7A11 translation, reducing cystine uptake and promoting ferroptosis.\",\n      \"method\": \"shRNA screen, RIP, translation assay, eIF3d pulldown, cystine uptake assay, in vivo lung cancer models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic screen plus multiple orthogonal mechanistic methods (RIP, pulldown, functional rescue) with in vivo validation\",\n      \"pmids\": [\"34609966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UFM1-mediated UFMylation of SLC7A11 promotes its protein stability; metformin inhibits this UFMylation, thereby reducing SLC7A11 protein levels, increasing intracellular Fe2+ and lipid ROS, and inducing ferroptosis in breast cancer cells.\",\n      \"method\": \"Co-IP/immunoprecipitation for UFMylation detection, SLC7A11 protein stability assays, ferroptosis markers (Fe2+, lipid ROS, GSH), in vivo nude-mouse tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — UFMylation shown by IP, stability assay, functional rescue; single lab, multiple methods\",\n      \"pmids\": [\"34162423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM3 E3 ubiquitin ligase directly interacts with SLC7A11 through its NHL domain and promotes SLC7A11 K11-linked ubiquitination at K37, leading to proteasome-mediated degradation of SLC7A11 and ferroptosis induction in NSCLC.\",\n      \"method\": \"Co-IP, domain mapping (NHL domain), ubiquitination assay (K11-linkage, K37 site), proteasome inhibitor rescue, in vivo tumor xenograft\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct interaction mapped to NHL domain, specific ubiquitin linkage and lysine identified, proteasome-dependence confirmed, in vivo validation\",\n      \"pmids\": [\"37978273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZRANB1 functions as an E3 ubiquitin ligase (not a deubiquitinase) for SLC7A11: it ubiquitinates and represses SLC7A11, inhibiting glutathione synthesis and promoting ferroptosis. Deletion of residues 463–584 abolishes ZRANB1's E3 activity.\",\n      \"method\": \"Whole-DUB sgRNA screen, ubiquitination assay, domain deletion mutagenesis, GSH/lipid peroxidation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide screen, E3 activity confirmed by mutagenesis of catalytic domain, mechanistic pathway validated\",\n      \"pmids\": [\"37831441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP52/PAN2 deubiquitylase interacts with SLC7A11/xCT and cleaves K48-linked ubiquitin chains at K4 and K12 of SLC7A11, thereby enhancing its protein stability and ferroptosis resistance in bladder cancer.\",\n      \"method\": \"siRNA screen of 96 DUBs, Co-IP, ubiquitin chain linkage analysis, site-specific mutagenesis (K4, K12), GSH/lipid peroxidation assays, in vivo xenograft\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased DUB screen, specific K48-chain cleavage at defined lysines confirmed by mutagenesis, in vivo validation\",\n      \"pmids\": [\"39392373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AMPKα1 directly phosphorylates ZDHHC8 at S299, strengthening ZDHHC8-SLC7A11 interaction; ZDHHC8 then catalyzes S-palmitoylation of SLC7A11 at Cys327, reducing its ubiquitination and stabilizing SLC7A11 protein to confer ferroptosis resistance in glioblastoma.\",\n      \"method\": \"Co-IP, phospho-site mutagenesis (S299), palmitoylation assay (acyl-RAC), Cys327 mutagenesis, ubiquitination assay, ZDHHC8 KD rescue with SLC7A11 OE\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — kinase phosphorylation of palmitoyl transferase, specific palmitoylation site (Cys327) identified, ubiquitination link established, functional rescue performed\",\n      \"pmids\": [\"38211651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OGT O-GlcNAcylates SLC7A11 at Ser26, a modification essential for SLC7A11 cystine import activity; USP8 stabilizes OGT by inhibiting K48-linked polyubiquitination at OGT K117, and SLK-mediated S716 phosphorylation of USP8 is required for USP8-OGT interaction.\",\n      \"method\": \"Co-IP, mass spectrometry, site-specific mutagenesis (Ser26, K117, S716), OGT KO rescue assay, cystine uptake assay, GSH measurement\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific O-GlcNAcylation site identified by MS and confirmed by mutagenesis, upstream kinase-DUB-transferase chain validated\",\n      \"pmids\": [\"37867237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Kynurenine (KYN), exported from IDO1-expressing cells, is imported by SLC7A11 into non-IDO1-expressing neighboring cells; intracellular KYN-derived metabolites suppress ferroptosis by ROS scavenging and activation of an NRF2-dependent, AHR-independent cell-protective pathway that includes SLC7A11 upregulation, propagating anti-ferroptotic signaling.\",\n      \"method\": \"Genetic KO of SLC7A11 and IDO1, metabolite supplementation, NRF2/AHR pathway analysis, ferroptosis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO experiments with metabolite rescue, pathway dissection using NRF2 vs AHR knockouts, multiple cell systems\",\n      \"pmids\": [\"35245456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLC7A11 acts as a molecular brake on efferocytosis in dendritic cells; pharmacological inhibition, deletion, or siRNA knockdown of Slc7a11 enhanced efferocytosis. Mechanistically, SLC7A11-deficient DCs became dependent on aerobic glycolysis using glucose from glycogen stores. In a diabetic wound-healing model, loss of SLC7A11 accelerated wound healing and reduced apoptotic cell load, linked to GDF15 release from efferocytic DCs.\",\n      \"method\": \"Pharmacological inhibition of SLC7A11, genetic KO, siRNA KD, transcriptomics of efferocytic DCs, db/db mouse wound model, metabolic flux studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological approaches, in vivo disease model validation, mechanistic metabolic link established\",\n      \"pmids\": [\"35614212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Slc7a11 deficiency in Fth-knockout cardiomyocytes reduces glutathione levels; overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis induced by iron overload.\",\n      \"method\": \"Conditional cardiomyocyte-specific KO (MCK-Cre, Myh6-Cre), Slc7a11 overexpression, GSH measurement, lipid peroxidation assay, ferrostatin-1 rescue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with two Cre lines, gain-of-function rescue, multiple ferroptosis markers, in vivo cardiac phenotype\",\n      \"pmids\": [\"32349646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATF4 directly activates SLC7A11 transcription; SLC7A11 maintains glutathione production to inhibit ferroptosis in hepatocytes. ATF4 ablation decreased SLC7A11 expression and increased ferroptosis susceptibility; ectopic SLC7A11 expression in ATF4-deficient hepatocytes and mouse livers reversed ferroptosis and hepatocarcinogenesis.\",\n      \"method\": \"Hepatocyte-specific ATF4 KO, ectopic SLC7A11 reconstitution in KO cells/mice, GSH measurement, lipid peroxidation assays, RNA-sequencing, HCC mouse models\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus single-gene rescue by SLC7A11 reconstitution, in vivo HCC models, RNA-seq pathway analysis\",\n      \"pmids\": [\"36996941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBx protein promotes EZH2-mediated H3K27me3 modification at the SLC7A11 promoter, suppressing SLC7A11 transcription and facilitating ferroptosis in hepatocytes; EZH2 inhibition or SLC7A11 overexpression rescued HBx-induced ferroptosis.\",\n      \"method\": \"ChIP for H3K27me3 at SLC7A11 promoter, Co-IP for HBx-EZH2 interaction, EZH2 inhibition, SLC7A11 OE rescue, ferroptosis markers (GSH, MDA, iron)\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with functional rescue, single lab\",\n      \"pmids\": [\"34615538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4A histone demethylase removes H3K9me3 from the SLC7A11 promoter, increasing SLC7A11 transcription and inhibiting ferroptosis in osteosarcoma; KDM4A knockdown reduced SLC7A11 expression and promoted ferroptosis.\",\n      \"method\": \"ChIP for H3K9me3 at SLC7A11 promoter, KDM4A KD, ferroptosis markers, in vivo metastasis model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms epigenetic mark change at SLC7A11 promoter, KD with functional ferroptosis readout, single lab\",\n      \"pmids\": [\"33689883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX2 directly binds the SLC7A11 promoter to activate its transcription; mutation of the SOX2 binding site in the SLC7A11 promoter reduced SLC7A11 expression and increased ferroptosis sensitivity. Oxidation at Cys265 of SOX2 inhibited its transcriptional activity toward SLC7A11.\",\n      \"method\": \"SLC7A11 promoter-reporter assay, SOX2 binding-site mutagenesis, Cys265 mutagenesis, ferroptosis assays, lung cancer stem-like cell models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter mutagenesis, site-specific oxidation mutagenesis, functional ferroptosis validation in cancer stem cells\",\n      \"pmids\": [\"34385181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NFATc1 transcriptionally upregulates SLC7A11 during RANKL-induced osteoclastogenesis; elevated SLC7A11 increases cystine transport leading to cystine accumulation upon TXNRD1 inhibition, causing disulfidptosis (not ferroptosis) specifically in osteoclast precursors.\",\n      \"method\": \"ChIP/transcriptional reporter for NFATc1-SLC7A11, SLC7A11 inhibitors, ferroptosis vs. disulfidptosis inhibitor panel, in vivo OVX mouse model, bone cystine measurement\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation confirmed by ChIP, mechanistic cell-death modality dissected with specific inhibitors, in vivo validation; single lab\",\n      \"pmids\": [\"37148740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3-mediated m6A modification of SLC7A11 mRNA is read by IGF2BP1, which competitively binds PABPC1 to block BTG2/CCR4-NOT complex recruitment, thereby inhibiting SLC7A11 mRNA deadenylation and enhancing mRNA stability and expression in hepatoblastoma.\",\n      \"method\": \"MeRIP-qPCR, RNA pulldown, RIP, RACE-PAT (deadenylation assay), dual luciferase reporter, m6A quantification\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal RNA biochemical methods (MeRIP, RIP, pulldown, deadenylation assay) establish mechanism in a single study\",\n      \"pmids\": [\"35522946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHGDH binds to RNA-binding protein PCBP2 and inhibits its ubiquitination degradation; stabilized PCBP2 in turn stabilizes SLC7A11 mRNA, increasing SLC7A11 expression and inhibiting ferroptosis in bladder cancer.\",\n      \"method\": \"Co-IP, mass spectrometry, RIP assay, ubiquitination assay, SLC7A11 mRNA stability assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and RIP with MS identification, ubiquitination assay, mRNA stability confirmed; single lab\",\n      \"pmids\": [\"36147463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNA-binding protein DAZAP1 interacts with the 3'UTR of SLC7A11 mRNA and positively regulates its stability, thereby inhibiting ferroptosis in HCC.\",\n      \"method\": \"RNA immunoprecipitation (RIP), 3'UTR binding assay, mRNA stability assay, ferroptosis assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and functional mRNA stability assay, single lab\",\n      \"pmids\": [\"33358859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEBPG directly binds the SLC7A11 promoter and transcriptionally activates SLC7A11 expression to suppress ferroptosis in ovarian cancer.\",\n      \"method\": \"CUT&Tag chromatin profiling, dual luciferase reporter assay, CEBPG KD, RNA-sequencing, ferroptosis assays, orthotopic mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag and luciferase reporter confirm direct promoter binding, functional validation with KD; single lab\",\n      \"pmids\": [\"37210575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EZH2 promotes SLC7A11 expression by repressing miR-125b-5p (which targets SLC7A11 3'UTR), thereby inhibiting ferroptosis in tongue squamous cell carcinoma; dual-luciferase assays confirmed EZH2 binding to miR-125b-5p promoter and miR-125b-5p binding to SLC7A11 3'UTR.\",\n      \"method\": \"Dual-luciferase reporter assays, RT-qPCR, Western blot, CCK-8, MDA assay\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase reporters validate two-step regulatory axis; single lab, limited methods beyond reporter assays\",\n      \"pmids\": [\"34614259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALKBH5 erases m6A modification on SLC7A11 mRNA, reducing its stability and expression, thereby promoting ferroptosis in colorectal cancer cells.\",\n      \"method\": \"m6A quantitative analysis, MeRIP-qPCR, mRNA stability assay (actinomycin D), ALKBH5 OE and SLC7A11 OE rescue, in vivo xenograft\",\n      \"journal\": \"Clinical & translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and mRNA stability assay confirm m6A-dependent regulation; single lab, in vivo validation\",\n      \"pmids\": [\"36820954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO m6A demethylase increases SLC7A11 expression in an m6A-YTHDF2-dependent manner; high FTO stabilizes SLC7A11 mRNA, counteracting ferroptosis in colorectal cancer.\",\n      \"method\": \"m6A modification analysis, YTHDF2 interaction studies, SLC7A11 mRNA stability assay, FTO KD/OE, in vivo CRC models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A reader/writer mechanism with mRNA stability assay; single lab\",\n      \"pmids\": [\"38600610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STAT6 competes with the acetyltransferase CBP to inhibit p53 acetylation, thereby transcriptionally restoring SLC7A11 expression and suppressing ferroptosis in lung epithelial cells during acute lung injury.\",\n      \"method\": \"ChIP, Co-IP for STAT6-CBP interaction, p53 acetylation assay, STAT6 KD/OE, SLC7A11 promoter-reporter, lung-specific STAT6 OE in ALI mouse models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP mechanistic data, in vivo ALI validation; single lab\",\n      \"pmids\": [\"35668064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPTBN2 interacts with SLC7A11 through its CH domain and connects it with motor protein Arp1, facilitating SLC7A11 membrane localization—a prerequisite for its cystine-uptake/GSH-synthesis function as System Xc-; SPTBN2 inhibition reduces membrane SLC7A11 and sensitizes NSCLC to ferroptosis.\",\n      \"method\": \"Co-IP (SPTBN2-SLC7A11-Arp1), membrane fractionation, ferroptosis assays (lipid ROS, GSH), in vivo cisplatin sensitivity model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain identification, membrane fractionation functional link, in vivo validation; single lab\",\n      \"pmids\": [\"38241838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Galectin-13 secreted from ferroptotic cells binds CD44 on neighboring cells and inhibits SLC7A11 plasma membrane localization, thereby reducing cystine uptake and propagating ferroptosis to neighboring cells. FOXK1, phosphorylated by PKCβII, drives Galectin-13 expression and secretion during ferroptosis.\",\n      \"method\": \"Galectin-13 secretion measurement, Co-IP (Galectin-13 with CD44), SLC7A11 membrane localization by fractionation/imaging, FOXK1 phosphorylation assay, functional ferroptosis propagation assays, synthetic mimetic peptide experiments\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (secretion assay, Co-IP, membrane fractionation, synthetic mimetic peptide) establish a new ferroptosis propagation mechanism\",\n      \"pmids\": [\"40246981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NINJ1 physically interacts with the xCT antiporter (SLC7A11); NINJ1 knockdown increases xCT protein levels and stability, enhancing cystine uptake, CoA, and GSH levels, thereby protecting against ferroptosis induced by xCT inhibitors specifically.\",\n      \"method\": \"Co-IP (NINJ1-xCT), NINJ1 KD/OE, xCT protein stability assay, cystine uptake assay, compound screen (PANKi, BSO, DEM), ferroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes physical interaction, mechanistic dissection with pharmacological probes; single lab\",\n      \"pmids\": [\"39424803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tumor suppressor BAP1 (H2A deubiquitinase) suppresses disulfidptosis through repression of SLC7A11: BAP1 suppresses SLC7A11 expression; SLC7A11 overexpression or additional cystine counteracts BAP1's protection against disulfidptosis; conversely, BAP1-mediated suppression of disulfidptosis is abrogated when SLC7A11-mediated cystine uptake is genetically or pharmacologically blocked.\",\n      \"method\": \"SLC7A11 KO/OE, disulfide bond accumulation assay (cytoskeleton proteins), cell death inhibitor panel, cystine supplementation, BAP1 OE\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (BAP1/SLC7A11 double manipulation), disulfidptosis-specific markers; single lab\",\n      \"pmids\": [\"39266549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CIC (Capicua) transcriptionally represses SLC7A11/xCT expression; non-phosphorylatable CIC (S173) that cannot interact with 14-3-3 showed stronger repressor function; CIC restoration in an oligodendroglioma line reduced SLC7A11 levels and extracellular glutamate release.\",\n      \"method\": \"CIC KO/re-expression, RNA-sequencing, extracellular glutamate measurement, CIC-S173 phospho-mutant analysis, 14-3-3 interaction studies\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with RNA-seq, functional glutamate release assay, phospho-mutant mechanistic dissection; single lab\",\n      \"pmids\": [\"36647117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD44 variant (CD44v8-10) stabilizes xCT/SLC7A11 protein on the cell surface, promoting reduced glutathione production and antioxidant defense; during endothelial-to-mesenchymal transition (EndMT), CD44v+ cells co-express high xCT and show enhanced survival dependent on this axis.\",\n      \"method\": \"Cell-surface xCT quantification, GSH measurement, pharmacological inhibition (sulfasalazine), in vivo Sugen5416/hypoxia PAH model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional protein stabilization shown pharmacologically and in vivo, but direct CD44v-xCT interaction mechanism inferred from prior cancer work; single lab\",\n      \"pmids\": [\"30897333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Secreted AGR2 from tumor-associated neutrophils binds CD98hc as its functional receptor and increases xCT/SLC7A11 transporter activity in a CD98hc-dependent manner, subsequently activating RhoA/ROCK2 cascade to promote CRC metastasis.\",\n      \"method\": \"Co-IP (AGR2-CD98hc), neutrophil-specific Agr2 KO mice, xCT activity assay, RhoA/ROCK2 pathway analysis, in vivo liver metastasis model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for receptor identification, genetic KO in vivo validation, pathway analysis; single lab\",\n      \"pmids\": [\"35086885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AhR (aryl hydrocarbon receptor) transcriptionally regulates SLC7A11 expression; pharmacological inactivation or genetic ablation of AhR suppresses SLC7A11 and enhances erastin-induced ferroptosis; the endogenous AhR ligand indole-3-pyruvate protects against ferroptosis through an AhR-SLC7A11 dependent mechanism. Post-translational modifications of SLC7A11 were also detected during ferroptosis.\",\n      \"method\": \"AhR KO/pharmacological inhibition, SLC7A11 transcription analysis, AhR ChIP (implied by transcriptional regulation), ferroptosis assays (lipid peroxidation), I3P supplementation\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological AhR manipulation with functional ferroptosis readouts; post-translational modification noted but not fully characterized; single lab\",\n      \"pmids\": [\"38641223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIAS4 directly binds SLC7A11 and facilitates its SUMOylation; KDM1A acts as a transcriptional activator of PIAS4; tanshinone IIA reduces KDM1A expression, thereby suppressing PIAS4 transcription, reducing SLC7A11 SUMOylation, and destabilizing SLC7A11 to promote ferroptosis in breast cancer.\",\n      \"method\": \"Ni-beads pull-down assay, Co-IP, luciferase assay, ChIP, SUMOylation assay, in vivo xenograft/lung metastasis models\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMOylation shown by pull-down and Co-IP, transcriptional axis confirmed by luciferase/ChIP; single lab\",\n      \"pmids\": [\"38615741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sulforaphane (SFN) directly targets p62 protein, enhancing p62-SLC7A11 protein-protein interaction, which promotes autolysosomal (lysosomal) degradation of SLC7A11 and triggers ferroptosis in osteosarcoma.\",\n      \"method\": \"p62-SLC7A11 Co-IP, lysosomal degradation inhibitor experiments, ferroptosis markers, in vivo subcutaneous and intratibial OS xenograft models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interaction, lysosomal pathway confirmed pharmacologically, in vivo validation; single lab\",\n      \"pmids\": [\"39657365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM3 binds SLC7A11 mRNA; sodium butyrate promotes RBM3 expression, which indirectly downregulates SLC7A11 and promotes ferroptosis in endometrial cancer cells.\",\n      \"method\": \"RNA pulldown and mass spectrometry (RBM3-SLC7A11 mRNA), transcriptome analysis, metabolome analysis, in vivo xenograft\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown/MS identifies RBM3-SLC7A11 mRNA interaction; functional axis confirmed with NaBu treatment; single lab\",\n      \"pmids\": [\"37170022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DUBA deubiquitinase stabilizes SLC7A11 protein in differentiated cells; elevated SLC7A11 in turn increases c-Myc expression through cysteine; undifferentiated (stem) cells express low DUBA/SLC7A11 and are more sensitive to ferroptosis.\",\n      \"method\": \"DUBA KD/OE, SLC7A11 ubiquitination assay, c-Myc expression analysis, cysteine supplementation rescue, sorafenib + c-Myc inhibitor combination assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay, c-Myc downstream link via cysteine, functional cell-death assay; single lab\",\n      \"pmids\": [\"37537342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FMRP promotes SLC7A11 expression via two mechanisms: (1) it catalyzes m6A modification of SLC7A11 mRNA in a METTL3-dependent manner, influencing translation; (2) FMRP interacts with splicing factor hnRNPM to modulate an exon-skip splicing event of SLC7A11 transcript, generating the SLC7A11-S variant that promotes ferroptosis resistance in breast cancer.\",\n      \"method\": \"RIP, METTL3-dependency analysis, Co-IP (FMRP-hnRNPM), splicing analysis, ferroptosis assays, clinical sample correlation\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal mechanisms (m6A and splicing) supported by RIP and Co-IP; single lab\",\n      \"pmids\": [\"39388855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 methylates adenine +1795 on SLC7A11 mRNA; the m6A reader IGF2BP2 recognizes this site and promotes SLC7A11 mRNA stability. Separately, METTL3 decreases SLC7A11 protein ubiquitination through the m6A/YTHDF2/SOCS2 axis. Both mechanisms require METTL3 methyltransferase activity.\",\n      \"method\": \"m6A site mapping (adenine +1795), RIP for IGF2BP2-SLC7A11 mRNA, mRNA stability assay, ubiquitination assay, SOCS2-YTHDF2 pathway analysis, in vivo HCC radiosensitivity models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific m6A site identified, two mechanistic branches (mRNA stability and protein ubiquitination) mapped; single lab\",\n      \"pmids\": [\"39799112\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC7A11/xCT is the light-chain subunit of the plasma-membrane system xc- antiporter (paired with SLC3A2/4F2hc via a disulfide bond) that exchanges extracellular cystine for intracellular glutamate 1:1, providing cysteine for glutathione biosynthesis and antioxidant defense; it additionally localizes to lysosomes where it mediates a slow H+ leak through downward flux of cystine and glutamate, regulating lysosomal pH and degradative capacity. SLC7A11 protein stability is dynamically controlled by a network of post-translational modifications—including K48-linked polyubiquitination (by E3 ligases SOCS2, TRIM3, ZRANB1) that targets it for proteasomal degradation, deubiquitination (by USP52, DUBA) that stabilizes it, S-palmitoylation at Cys327 (by ZDHHC8, itself activated by AMPKα1 phosphorylation) that protects against ubiquitination, O-GlcNAcylation at Ser26 (by OGT, stabilized by USP8) that is essential for cystine import activity, and SUMOylation (by PIAS4) that promotes stability—as well as by lysosomal degradation through a p62-SLC7A11 interaction and by membrane trafficking regulated by SPTBN2-Arp1. Its transcription is activated by ATF4, NRF2, SOX2, CEBPG, NFATc1, STAT6 (via p53 acetylation suppression), AhR, and STAT1, and repressed by BAP1-mediated H2A deubiquitination, EZH2/H3K27me3, KDM4A-reversed H3K9me3, p53, ATF3, and CIC; SLC7A11 mRNA stability and translation are regulated by multiple RNA-binding proteins (RBMS1 via eIF3d bridging of 5'/3'-UTRs, DAZAP1, RBM3, FMRP/hnRNPM) and m6A modifications (METTL3/IGF2BP1/2, FTO/YTHDF2, ALKBH5). Physiologically, high SLC7A11 suppresses ferroptosis by maintaining GSH, imports kynurenine to propagate anti-ferroptotic NRF2 signaling, acts as a brake on efferocytosis in dendritic cells (shifting metabolism toward glycolysis), and regulates extracellular glutamate in the CNS; ferroptotic cells can propagate cell death to neighbors by secreting Galectin-13, which inhibits SLC7A11 membrane localization via CD44 binding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC7A11 (xCT) is the substrate-specific light-chain subunit of the plasma-membrane cystine/glutamate antiporter system xc-, disulfide-linked to the heavy chain 4F2hc/SLC3A2, exchanging extracellular cystine for intracellular glutamate to supply cysteine for glutathione synthesis and antioxidant defense [#1]. Through this function it is the central cellular determinant of ferroptosis sensitivity: high SLC7A11 maintains GSH and suppresses lipid peroxidation, while its loss or inhibition triggers ferroptotic death across diverse tissues including cardiomyocytes, hepatocytes, and tumors [#14, #15]. Beyond the cell surface, SLC7A11 also resides on lysosomes where downward flux of cystine and glutamate mediates a slow H+ leak that regulates lysosomal pH and degradative capacity; its deficiency causes over-acidification, impaired degradation, and facilitates α-synuclein aggregation in neurons [#0]. SLC7A11 abundance and activity are governed by an exceptionally dense post-translational network: K48/K11-linked polyubiquitination by E3 ligases SOCS2, TRIM3, and ZRANB1 drives proteasomal degradation [#4, #7, #8], while deubiquitinases USP52 and DUBA, S-palmitoylation at Cys327 by AMPKα1-activated ZDHHC8, O-GlcNAcylation at Ser26 by OGT (essential for cystine import), and PIAS4-mediated SUMOylation stabilize the protein or its transport function [#9, #10, #11, #36, #39]. Membrane delivery requires SPTBN2-Arp1 trafficking, and surface localization is antagonized by secreted Galectin-13 acting through CD44 to propagate ferroptosis to neighboring cells [#28, #29]. Transcriptionally, SLC7A11 is activated by ATF4, SOX2, CEBPG, NFATc1, STAT6, and AhR and repressed by the BAP1/PRC1 H2A-ubiquitination axis, EZH2/H3K27me3, and CIC [#15, #18, #23, #3, #16, #32], and its mRNA is further tuned by RNA-binding proteins (RBMS1, DAZAP1) and m6A machinery (METTL3/IGF2BP1/2, FTO/YTHDF2, ALKBH5) [#5, #20, #25, #41]. Functionally, SLC7A11 imports kynurenine to propagate anti-ferroptotic NRF2 signaling, acts as a metabolic brake on dendritic-cell efferocytosis, and regulates CNS extracellular glutamate; excessive cystine uptake under thioredoxin-reductase inhibition can instead drive disulfidptosis [#12, #13, #19, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the core biochemical identity of SLC7A11 as the cystine/glutamate antiporter light chain, defining how it supplies the rate-limiting precursor for glutathione synthesis.\",\n      \"evidence\": \"Synthesis of transport assays, disulfide-linkage biochemistry, and pharmacological inhibition in neuronal systems\",\n      \"pmids\": [\"21369940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the transporter's role in regulated cell death\", \"Structural basis of cystine/glutamate exchange not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SLC7A11 transcriptional suppression to immunotherapy and radiotherapy efficacy, establishing it as a therapeutically targetable node controlling tumor ferroptosis.\",\n      \"evidence\": \"In vivo tumor models with IFNγ neutralization, ATM inhibition, and ferroptosis modulation\",\n      \"pmids\": [\"31554642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription factors downstream of IFNγ/ATM at the SLC7A11 promoter not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined epigenetic and surface-protein control of SLC7A11, showing BAP1-mediated H2A deubiquitination represses transcription while CD44v8-10 stabilizes surface protein to govern antioxidant defense.\",\n      \"evidence\": \"ChIP for H2Aub, BAP1/PRC1 genetic manipulation, ferroptosis assays; cell-surface xCT quantification and GSH measurement in EndMT/PAH models\",\n      \"pmids\": [\"30907299\", \"30897333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical CD44v-xCT interaction inferred rather than mapped in [#33]\", \"How dynamic H2Aub balance is set at the promoter not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated in vivo that SLC7A11 sustains GSH to prevent iron-overload ferroptosis in cardiomyocytes, extending its protective role beyond cancer to organ physiology.\",\n      \"evidence\": \"Cardiomyocyte-specific conditional KO and overexpression with ferrostatin-1 rescue\",\n      \"pmids\": [\"32349646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulators of cardiac SLC7A11 not defined\", \"Did not address lysosomal function\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Opened the mRNA-stability layer of SLC7A11 regulation, showing 3'UTR-binding RBPs tune transcript abundance and thereby ferroptosis sensitivity.\",\n      \"evidence\": \"RIP, 3'UTR binding and mRNA stability assays for DAZAP1 in HCC\",\n      \"pmids\": [\"33358859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP/RIP without reciprocal validation\", \"Direct binding motif not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ubiquitin-dependent degradation of SLC7A11 by E3 ligase SOCS2, establishing the first substrate-receptor mechanism targeting the transporter for proteasomal turnover.\",\n      \"evidence\": \"Co-IP with domain mapping (SH2/SOCS-BOX), elongin B/C recruitment, ubiquitination assays, in vivo radiosensitivity models\",\n      \"pmids\": [\"35995846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counteracting deubiquitinases for SOCS2-driven chains not identified here\", \"Physiological trigger for SOCS2 engagement unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed translational control of SLC7A11, with RBMS1 bridging 5'/3'-UTRs via eIF3d to enhance translation and govern cystine uptake.\",\n      \"evidence\": \"shRNA screen, RIP, translation and eIF3d pulldown assays, cystine uptake, in vivo lung cancer models\",\n      \"pmids\": [\"34609966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling RBMS1 activity not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded epigenetic and post-translational regulation, showing histone-modification enzymes (EZH2/H3K27me3, KDM4A/H3K9me3), SOX2 transcriptional activation, miRNA axes, and UFMylation each set SLC7A11 levels.\",\n      \"evidence\": \"ChIP for histone marks, promoter-reporter and binding-site mutagenesis, dual-luciferase miRNA assays, UFMylation IP and stability assays\",\n      \"pmids\": [\"34615538\", \"33689883\", \"34385181\", \"34614259\", \"34162423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several axes rest on single-lab reporter assays\", \"Hierarchy among competing transcriptional inputs unresolved\", \"UFM1 ligase machinery for SLC7A11 not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established non-canonical signaling and immunometabolic roles: SLC7A11 imports kynurenine to propagate NRF2-dependent anti-ferroptotic signaling and acts as a metabolic brake on dendritic-cell efferocytosis.\",\n      \"evidence\": \"Genetic KO of SLC7A11/IDO1 with metabolite rescue and NRF2/AHR dissection; pharmacological/genetic SLC7A11 ablation, metabolic flux, db/db wound-healing model\",\n      \"pmids\": [\"35245456\", \"35614212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for kynurenine transport by SLC7A11 not defined\", \"Link between transporter activity and glycolytic rewiring mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the m6A and RBP layer of mRNA stability control, with METTL3/IGF2BP1 blocking deadenylation and PCBP2 (stabilized by PHGDH) and additional factors setting transcript half-life.\",\n      \"evidence\": \"MeRIP, RIP, RNA pulldown, deadenylation (RACE-PAT) and mRNA stability assays\",\n      \"pmids\": [\"35522946\", \"36147463\", \"35086885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanisms not cross-validated\", \"Interplay among multiple m6A writers/readers on the same transcript unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped specific ubiquitin linkages and lysine sites for SLC7A11 degradation (TRIM3 K11/K37, ZRANB1) and opposing deubiquitination/stabilization (DUBA, OGT O-GlcNAcylation at Ser26 with USP8/SLK control), defining a precise PTM grammar for transporter turnover and activity.\",\n      \"evidence\": \"Co-IP, domain mapping, linkage- and site-specific ubiquitination and O-GlcNAcylation assays, mass spectrometry, functional rescue, in vivo xenografts\",\n      \"pmids\": [\"37978273\", \"37831441\", \"37537342\", \"37867237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk between distinct ubiquitin linkages on SLC7A11 not integrated\", \"Physiological cues directing each ligase/DUB to the substrate unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened transcriptional regulation across tissues (ATF4, CEBPG, NFATc1, STAT6, AhR, CIC) and tied SLC7A11 to distinct death modalities, including NFATc1-driven disulfidptosis in osteoclast precursors and CIC-controlled CNS glutamate release.\",\n      \"evidence\": \"Tissue-specific KO/rescue, ChIP/CUT&Tag, promoter-reporter, p53-acetylation and 14-3-3/phospho-mutant analyses, death-modality inhibitor panels, in vivo disease models\",\n      \"pmids\": [\"36996941\", \"37210575\", \"37148740\", \"35668064\", \"38641223\", \"36647117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several transcriptional axes are single-lab\", \"Conditions that switch SLC7A11 output between ferroptosis protection and disulfidptosis vulnerability not unified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved palmitoylation- and SUMOylation-based stabilization (AMPKα1-ZDHHC8-Cys327; PIAS4) and deubiquitinase USP52 control, plus trafficking by SPTBN2-Arp1 as a prerequisite for surface transport activity.\",\n      \"evidence\": \"Acyl-RAC palmitoylation and SUMOylation assays, site-specific mutagenesis (Cys327), DUB siRNA screen, Co-IP/membrane fractionation, in vivo models\",\n      \"pmids\": [\"38211651\", \"38615741\", \"39392373\", \"38241838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between palmitoylation, ubiquitination, and trafficking not temporally ordered\", \"Some interactions (SPTBN2, PIAS4) rest on single-lab Co-IP\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended mRNA and protein regulation through additional m6A enzymes and RBPs (FTO/YTHDF2, FMRP/hnRNPM splicing, METTL3/IGF2BP2 and METTL3/YTHDF2/SOCS2) and identified NINJ1 as a physical interactor limiting xCT stability.\",\n      \"evidence\": \"m6A site mapping, RIP, splicing and stability assays, Co-IP, ubiquitination assays, in vivo models\",\n      \"pmids\": [\"38600610\", \"39388855\", \"39799112\", \"39424803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Multiple parallel m6A mechanisms not reconciled\", \"NINJ1-xCT mechanism rests on single-lab Co-IP\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovered an organelle-level function—lysosomal H+ leak via SLC7A11 controlling lysosomal pH, degradation, and neuronal α-synuclein aggregation—and a non-cell-autonomous ferroptosis propagation circuit through secreted Galectin-13/CD44 inhibition of xCT membrane localization.\",\n      \"evidence\": \"Orphan lysosomal-protein screen, KO/inhibition, lysosomal pH measurement and rescue; Galectin-13 secretion, CD44 Co-IP, membrane fractionation, FOXK1/PKCβII phosphorylation, mimetic-peptide assays\",\n      \"pmids\": [\"40280132\", \"40246981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of lysosomal H+ leak vs plasma-membrane antiport not defined\", \"How surface vs lysosomal pools are partitioned and regulated unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dozens of competing transcriptional, RNA-level, and post-translational inputs are integrated to set SLC7A11 surface vs lysosomal abundance in a given cell state, and the structural basis distinguishing its antiport, kynurenine import, and lysosomal H+-leak functions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of regulatory hierarchy\", \"No structure linking transport modes\", \"Determinants of plasma-membrane vs lysosomal localization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 11, 12, 28]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 28, 29, 33]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3, 14, 15, 29]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 12, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [12, 35]}\n    ],\n    \"complexes\": [\n      \"system xc- (SLC7A11/SLC3A2 antiporter)\"\n    ],\n    \"partners\": [\n      \"SLC3A2\",\n      \"SOCS2\",\n      \"TRIM3\",\n      \"ZRANB1\",\n      \"USP52\",\n      \"ZDHHC8\",\n      \"SPTBN2\",\n      \"CD44\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}