{"gene":"MAFF","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1993,"finding":"MafF encodes a small nuclear bZIP protein lacking the amino-terminal acidic transactivation domain present in c-Maf; when overexpressed via retroviral vector in CEF cells, MafF did not induce morphological transformation but induced colony formation in soft agar with very low efficiency; MafK protein was detected predominantly in nuclei by immunostaining.","method":"Retroviral overexpression in CEF cells, soft-agar colony assay, immunostaining with specific antibody, structural analysis of cDNA clones","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — retroviral OE with defined phenotypic readout and nuclear localization confirmed by antibody; single lab, two orthogonal methods","pmids":["8361754"],"is_preprint":false},{"year":1999,"finding":"Human MafF (hMafF) binds specifically to the US-2 element in the oxytocin receptor (OTR) gene promoter, as shown by yeast one-hybrid screening and electrophoretic mobility shift assay (EMSA); hMafF is an 18-kDa protein with a leucine zipper but no transactivation domain, preferentially expressed in term myometrium.","method":"Yeast one-hybrid screening of term myometrium cDNA library, EMSA, Northern hybridization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA-binding demonstrated by two orthogonal methods (yeast one-hybrid + EMSA); single lab","pmids":["10527846"],"is_preprint":false},{"year":1999,"finding":"Murine MafF is dispensable for development: homozygous mafF null mice are born at normal Mendelian ratios with no obvious functional deficiencies, even in tissues where other small Maf proteins are low. The lacZ-knockin revealed prominent mafF expression in gut, lung, liver, heart outflow tract, cartilage, bone membrane, and skin, but not in hematopoietic cells at any developmental stage. mafF is regulated by three distinct promoters.","method":"Gene targeting (mafF null mice), lacZ knock-in reporter, developmental expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with Mendelian analysis, lacZ reporter for spatial expression, multiple orthogonal methods in one rigorous study","pmids":["10409670"],"is_preprint":false},{"year":2002,"finding":"MafF can form homodimers and high-affinity heterodimers with CNC-bZip family members Nrf1, Nrf2, and NF-E2. MafF homodimers do not repress transcription (unlike MafG/MafK homodimers) on gamma-globin, beta-globin, and GCSl promoters in multiple cell lines, while MafF/CNC heterodimers act as weak transcriptional activators. MafF shows a specific regulatory role in combination with Jun at the GCSl promoter.","method":"Reporter gene assays in multiple cell lines, protein–protein interaction studies, promoter-reporter constructs","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with multiple promoters and dimerization partners; single lab but multiple orthogonal approaches","pmids":["12490281"],"is_preprint":false},{"year":2002,"finding":"mafF transcript is differentially induced by electrophile-response-element (EpRE) activators PDTC and PEITC (but not tBHQ) in HepG2 cells, and this induction is transcriptionally mediated; mafF is induced to a greater extent than mafG or mafK. The induction by tBHQ failure suggests that small Maf upregulation is not an absolute requirement for EpRE-mediated gene expression.","method":"RT-PCR/Northern blot in multiple cell lines, actinomycin D transcription inhibition assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcriptional induction confirmed by actinomycin D block; replicated across cell lines but no direct mechanistic dissection of MAFF protein function","pmids":["11772409"],"is_preprint":false},{"year":2005,"finding":"MAFF mRNA and protein are rapidly induced (within 30 min) by IL-1β and TNF in PHM1-31 myometrial cells at the transcriptional level (actinomycin D-sensitive); the highly homologous MAFG and MAFK transcripts and proteins are not modulated by these cytokines, indicating a cytokine-specific regulation unique to MAFF.","method":"RT-PCR time-course, actinomycin D inhibition, Western blot with MAFF-specific antiserum","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional induction confirmed by chemical inhibitor and protein-level validation; single lab, two orthogonal methods","pmids":["16371591"],"is_preprint":false},{"year":2006,"finding":"A novel protein MIP (MafF Interacting Protein) physically interacts with hMafF via its coiled-coil domain binding the leucine zipper of hMafF in vitro and in vivo; this interaction causes translocation of MIP from the cytoplasm to the nucleolus in HeLa cells. Co-expression of hMafF and MIP activates US2-element-driven transcription, whereas either alone has no effect, establishing MIP as a co-activator of hMafF.","method":"Co-immunoprecipitation (in vivo), in vitro binding assay, subcellular localization imaging, promoter-reporter assay in HeLa cells","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding confirmed in vitro and in vivo, functional co-activation shown by reporter assay; single lab","pmids":["16549056"],"is_preprint":false},{"year":2009,"finding":"Using a recombinant yeast detection system, MIP was confirmed to enable hMafF-dependent transactivation of US2-driven reporter (LacZ): only the co-presence of both MIP and hMafF activates the reporter, corroborating the co-activator role of MIP for hMafF.","method":"Recombinant yeast reporter system (beta-galactosidase quantitative assay), plasmid transformation of YM4271 yeast","journal":"Journal of microbiological methods","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method, confirmatory of prior finding in a heterologous system","pmids":["19723544"],"is_preprint":false},{"year":2016,"finding":"sMafs (MafF, MafG, MafK) are bZIP transcription factors that: (1) form homodimers that act as transcriptional repressors (lacking activation domain); (2) form obligatory heterodimers with CNC proteins (NF-E2 p45, Nrf1, Nrf2, Nrf3) and Bach proteins (Bach1, Bach2), which cannot bind DNA as monomers, making sMafs indispensable partners; (3) participate in transcriptional activation or repression depending on heterodimeric partner and context.","method":"Review synthesizing genetic analyses in mice, structural studies, and biochemical data across multiple labs","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Strong — review consolidating independently replicated genetic and biochemical findings across multiple labs; established mechanistic framework","pmids":["27058431"],"is_preprint":false},{"year":2019,"finding":"MAFF directly binds the promoters of CXCL1 and CSF3 in PHM1-31 myometrial cells, as shown by ChIP, and MAFF knockdown significantly decreases CXCL1 and CSF3 transcript and protein levels. MAFF-dependent cytokine production in myometrial cells can modulate cytokine and matrix metalloproteinase gene expression in THP-1 monocytic cells in a paracrine manner.","method":"siRNA knockdown, ChIP, RT-PCR, ELISA, paracrine co-culture assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter occupancy by ChIP plus loss-of-function with transcript and protein readouts; single lab","pmids":["30669188"],"is_preprint":false},{"year":2021,"finding":"MAFF forms a heterodimer with BACH1 that directly binds the LDLR promoter MAF recognition element (MARE) under inflammatory conditions (LPS stimulation), transcriptionally downregulating LDLR expression. Under non-inflammatory conditions, MAFF positively correlates with LDLR. BACH1 assists MAFF in inflammatory contexts, as revealed by ChIP-mass spectrometry.","method":"ChIP-sequencing, ChIP-mass spectrometry, siRNA knockdown, overexpression in mouse and human liver cells, KO mouse experiments, correlation in 600 CAD patients","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-MS identified BACH1 as MAFF partner; ChIP-seq confirmed promoter binding; validated by KO and KD with in vitro and in vivo readouts across multiple systems","pmids":["33626882"],"is_preprint":false},{"year":2021,"finding":"MAFF heterodimerizes with BACH1 to directly activate IL11 transcription under hypoxic conditions in breast cancer cells; IL11 activates STAT3 signaling; inhibition of IL11 phenocopies MAFF inhibition in suppressing metastasis. MAFF expression is induced by hypoxia (HIF target).","method":"ChIP-sequencing, RNA-sequencing, siRNA knockdown, overexpression, invasion assay, metastasis mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — combined ChIP-seq and RNA-seq identified IL11 as direct target; functional rescue experiments confirmed pathway; multiple orthogonal methods","pmids":["34262028"],"is_preprint":false},{"year":2021,"finding":"MafF suppresses transcription from the HBV core promoter by physically binding to the HBV core promoter region (ChIP analysis) and competitively inhibiting HNF-4α binding to an overlapping sequence in enhancer II (EnhII). MafF loss (via CRISPR or siRNA) increases HBV core RNA and pgRNA levels. MafF expression is induced by IL-1β or TNF-α in an NF-κB-dependent manner in hepatocytes.","method":"siRNA library screen with HBV/NanoLuc reporter, CRISPR/Cas9 KO, ChIP analysis, overexpression with promoter mutation, siRNA in primary hepatocytes","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding to viral promoter by ChIP, competitive inhibition with HNF-4α, loss-of-function by two methods (CRISPR + siRNA), promoter mutagenesis; multiple orthogonal experiments","pmids":["33980595"],"is_preprint":false},{"year":2021,"finding":"miR-320a directly targets MafF mRNA (identified by RIP-Seq and confirmed by luciferase reporter assay), reducing MafF protein levels in pancreatic β cells; overexpression of miR-320a increases ROS, inhibits proliferation, and induces apoptosis of β cells, effects attributable to MafF suppression.","method":"RIP-Seq, luciferase reporter assay, Western blot, AAV8-mediated β cell-specific overexpression/inhibition, islet transplantation, hyperglycemic clamp","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-Seq + luciferase confirms direct miRNA targeting; in vivo validation in mice; single lab","pmids":["34631276"],"is_preprint":false},{"year":2024,"finding":"BAP1 (a nuclear deubiquitinating enzyme) binds to MAFF and deubiquitylates it, primarily removing K48-linked ubiquitin chains, thereby stabilizing MAFF protein. Stabilized MAFF upregulates DUSP5 expression, resulting in inhibition of ERK phosphorylation, which suppresses colorectal cancer cell growth.","method":"Quantitative proteomics, DUB expression library screening, Co-IP, ubiquitination assay, RNA sequencing, gain-of-function/loss-of-function in CRC cells and xenografts","journal":"European journal of cancer","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical deubiquitination assay, direct binding by Co-IP, downstream pathway defined by RNA-seq + phosphorylation readout, in vivo validation; multiple orthogonal methods","pmids":["39151323"],"is_preprint":false},{"year":2024,"finding":"MAFF directly regulates SLC7A11, CDK6, and CDKN2C transcription (by ChIP-seq), promoting ferroptosis (via SLC7A11 repression) and preventing cell cycle progression from G1 to S (via CDK6/CDKN2C). The cAMP/PKA/CREB1 pathway upregulates MAFF expression in response to cisplatin or ionizing radiation in LUAD.","method":"CRISPR screens (cell and murine models), single-cell RNA-seq, ChIP-seq, RNA-seq, cellular and xenograft models","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR functional screen + ChIP-seq identifies direct transcriptional targets; upstream pathway defined; validated in vivo; multiple orthogonal methods","pmids":["38266355"],"is_preprint":false},{"year":2024,"finding":"MAFF binds to the ZNF711 promoter and, together with its interacting partner BATF3 (confirmed by co-IP and immunofluorescence co-localization), represses ZNF711 transcription; BATF3 knockdown alone or combined with MAFF knockdown produce similar effects on ZNF711 expression and apoptosis in ovarian cancer cells.","method":"Dual-luciferase reporter assay, ChIP-PCR, Co-IP, immunofluorescence, siRNA knockdown, xenograft model","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and luciferase; BATF3 interaction confirmed by Co-IP and IF; single lab","pmids":["38908812"],"is_preprint":false},{"year":2025,"finding":"HDAC6 suppresses MAFF expression through deacetylation of MAFF, removing its inhibitory effect on KLF5 transcription; MAFF directly represses KLF5 promoter activity (confirmed by ChIP and dual luciferase assay). Loss of MAFF-mediated KLF5 repression enhances fibrosis and inflammatory response in lupus nephritis.","method":"ChIP, dual luciferase reporter assay, cell transfection (overexpression/knockdown), in vivo MRL/lpr mouse model, biochemical analyses","journal":"Renal failure","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms MAFF binding to KLF5 promoter; HDAC6-mediated deacetylation links to MAFF regulation; single lab","pmids":["39412062"],"is_preprint":false},{"year":2025,"finding":"MAFF heterodimerizes with BACH1 to directly transcriptionally activate CLCF1 (identified by CUT&Tag + RNA-seq), which subsequently triggers STAT3 signaling; MAFF overexpression reduces hepatocyte apoptosis and inflammation in hepatic ischemia-reperfusion injury in mice.","method":"CUT&Tag sequencing, RNA-seq, adenovirus-mediated overexpression in mice, in vitro hepatocyte assays","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag identifies direct CLCF1 target; BACH1 heterodimer established; downstream STAT3 pathway validated; single lab","pmids":["40169936"],"is_preprint":false},{"year":2025,"finding":"YTHDC1 (m6A reader) mediates nuclear export and stabilization of MAFF mRNA and promotes MAFF translation; MAFF in turn transcriptionally activates VMP1. In hepatocytes, the YTHDC1-MAFF-VMP1 axis protects against oxidative stress in hepatic ischemia/reperfusion injury.","method":"Knockdown/overexpression of YTHDC1 and MAFF, VMP1 functional rescue, in vitro H/R model, in vivo I/R mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiments establish pathway order; YTHDC1 role in MAFF mRNA stability/nuclear export defined; single lab","pmids":["40054588"],"is_preprint":false},{"year":2025,"finding":"ZNF655 promotes nuclear translocation of MAFF in ovarian cancer cells; nuclear MAFF then directly binds the CCND1 promoter and transcriptionally activates CCND1, promoting cell proliferation and stemness. Rescue experiments confirm CCND1 is required for ZNF655-dependent effects.","method":"ZNF655 depletion, MAFF nuclear translocation analysis (immunofluorescence), promoter binding (ChIP implied by 'direct binding'), rescue experiments, xenograft models","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — nuclear translocation and promoter binding described but full methodological detail absent from abstract; single lab, single publication","pmids":["41088232"],"is_preprint":false},{"year":2025,"finding":"MAFF suppresses YAP1 nuclear translocation in NSCLC cells; MAFF overexpression reduces YAP1, VEGF, and CTGF expression and inhibits angiogenesis both in vitro and in nude mouse xenograft models.","method":"Western blot, immunofluorescence (YAP1 localization), overexpression experiments, xenograft mouse model, IHC of clinical samples","journal":"PeerJ","confidence":"Low","confidence_rationale":"Tier 3 / Weak — YAP1 nuclear translocation suppression by IF established, but mechanism of how MAFF suppresses YAP1 translocation not defined; single lab","pmids":["41287850"],"is_preprint":false},{"year":2026,"finding":"MAFF directly transcriptionally activates SLC11A2 and NCOA4 (expanding the labile iron pool) and represses CPT2, FASN, and SCD1 (shifting lipid metabolism toward PUFAs), as established by combined RNA-seq and ChIP-seq; these metabolic changes promote ferroptosis susceptibility and tumor invasion in breast cancer cells.","method":"RNA-sequencing, ChIP-sequencing, functional ferroptosis assays, lipid metabolite measurement, loss-of-function/gain-of-function experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq + RNA-seq identifies direct transcriptional targets; mechanistic consequences (iron pool, lipid peroxidation) validated by metabolite and cell death assays; multiple orthogonal methods","pmids":["42209456"],"is_preprint":false},{"year":2026,"finding":"MAFF acts as a direct transcriptional repressor of GATA4; GATA4 in turn transcriptionally activates MLKL (necroptotic executioner). MAFF depletion reactivates the GATA4-MLKL axis, triggering necroptosis in pancreatic cancer cells. Pharmacological inhibition of necroptosis or knockdown of GATA4/MLKL reverses the growth-inhibitory effects of MAFF silencing.","method":"RNA-sequencing, GSEA, MAFF KO/overexpression, genetic knockdown of GATA4 and MLKL, pharmacological necroptosis inhibition, in vivo tumor models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis established by double-KD rescue; pathway defined by RNA-seq + GSEA; single lab","pmids":["42153582"],"is_preprint":false},{"year":2026,"finding":"MAFF directly binds the promoter of AKR1C1 and transcriptionally activates it (confirmed by dual-luciferase reporter assay); the MAFF-AKR1C1 axis leads to MDA accumulation and elevated lipid ROS, inhibiting ferroptosis and promoting pancreatic cancer progression.","method":"Dual-luciferase reporter assay, bioinformatics (ELMER), in vitro cellular assays, xenograft models, transcriptome sequencing","journal":"QJM","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by luciferase assay; ferroptotic consequences validated in vitro and in vivo; single lab","pmids":["41206944"],"is_preprint":false},{"year":2026,"finding":"In sow myometrium, NRF2 and MAFF directly target the promoters of PTGS2 and OXTR (contraction-associated genes), confirmed by dual-luciferase reporter assays; melatonin acting through the MT2 receptor activates PKC, which regulates NRF2 and MAFF expression to enhance myometrial contractility. Silencing MAFF in melatonin-treated cells reduces contraction-associated protein expression.","method":"Dual-luciferase reporter assay, siRNA knockdown, PKC pathway inhibition, collagen gel contraction assay, in vivo sow parturition experiments","journal":"Journal of pineal research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct MAFF promoter binding on PTGS2 and OXTR confirmed by luciferase assay; upstream pathway (MT2-PKC) defined; single lab","pmids":["41854048"],"is_preprint":false}],"current_model":"MAFF is a small bZIP transcription factor that lacks an intrinsic transactivation domain and functions as an obligatory heterodimeric partner for CNC-family (Nrf1, Nrf2, NF-E2) and Bach-family (Bach1, Bach2) proteins, which cannot bind DNA alone; MAFF homodimers act as transcriptional repressors, while heterodimers activate or repress target genes (including LDLR, IL11, CLCF1, CXCL1, CSF3, SLC7A11, CDK6, AKR1C1, GATA4, SLC11A2, and NCOA4) depending on partner and cellular context; MAFF protein stability is regulated by K48-linked ubiquitination and deubiquitination by BAP1, its mRNA is stabilized and exported by the m6A reader YTHDC1, its expression is rapidly induced transcriptionally by IL-1β/TNF via NF-κB, and it is post-translationally suppressed by HDAC6-mediated deacetylation, collectively positioning MAFF as a context-dependent transcriptional switch linking inflammatory signaling, iron/lipid metabolism, ferroptosis, and cell cycle regulation."},"narrative":{"mechanistic_narrative":"MAFF is a small nuclear bZIP transcription factor that lacks an intrinsic transactivation domain and functions as a context-dependent transcriptional switch coordinating inflammatory, metabolic, and cell-fate programs [PMID:8361754, PMID:27058431]. It dimerizes through its leucine zipper: homodimers are transcriptionally inert or repressive, whereas obligatory heterodimers with CNC-family proteins (Nrf1, Nrf2, NF-E2) and Bach-family proteins (Bach1, Bach2)—which cannot bind DNA alone—activate or repress target genes at MAF recognition elements depending on partner and cellular context [PMID:12490281, PMID:27058431]. Through BACH1 heterodimers, MAFF directly binds promoters to repress LDLR under inflammation [PMID:33626882] and to activate IL11 and CLCF1, both feeding STAT3 signaling in cancer and liver injury [PMID:34262028, PMID:40169936], while NRF2 partnership drives contraction-associated genes PTGS2 and OXTR in myometrium [PMID:41854048]. MAFF directly controls a broad transcriptional program governing ferroptosis and lipid/iron metabolism—repressing SLC7A11 and activating SLC11A2, NCOA4, and AKR1C1 while reprogramming lipid metabolism enzymes [PMID:38266355, PMID:42209456, PMID:41206944]—and cell-cycle and death pathways via CDK6/CDKN2C, GATA4-MLKL necroptosis, and DUSP5-mediated ERK suppression [PMID:39151323, PMID:38266355, PMID:42153582]. MAFF expression and stability are heavily regulated: it is rapidly and transcriptionally induced by IL-1β/TNF through NF-κB [PMID:16371591, PMID:33980595], its mRNA is exported and stabilized by the m6A reader YTHDC1 [PMID:40054588], and its protein is stabilized by BAP1-mediated removal of K48-linked ubiquitin and suppressed by HDAC6-mediated deacetylation [PMID:39151323, PMID:39412062]. Loss-of-function in mice shows MAFF is dispensable for development [PMID:10409670].","teleology":[{"year":1993,"claim":"Established MAFF as a small bZIP protein lacking the acidic transactivation domain of large Mafs, raising the question of how it could regulate transcription at all.","evidence":"Retroviral overexpression in CEF cells with soft-agar assay and structural analysis of cDNA, nuclear localization by immunostaining","pmids":["8361754"],"confidence":"Medium","gaps":["No DNA target or dimerization partner identified","Weak transformation phenotype not mechanistically explained"]},{"year":1999,"claim":"Showed MAFF binds a defined promoter element (US-2 of the oxytocin receptor gene) and is enriched in term myometrium, giving the protein a concrete DNA-binding target.","evidence":"Yeast one-hybrid screening of myometrium cDNA library, EMSA, Northern hybridization","pmids":["10527846"],"confidence":"Medium","gaps":["Did not establish whether binding required a heterodimeric partner","No functional transcriptional readout in cells"]},{"year":1999,"claim":"Genetic deletion in mice resolved whether MAFF is individually essential, showing it is dispensable for development while mapping its broad tissue expression via three promoters.","evidence":"MafF null mice with Mendelian analysis and lacZ knock-in reporter","pmids":["10409670"],"confidence":"High","gaps":["Redundancy with MafG/MafK not directly tested here","No molecular target defined in vivo"]},{"year":2002,"claim":"Defined MAFF's dimerization logic, distinguishing it from other small Mafs: its homodimers are not repressive, while CNC heterodimers (Nrf1/Nrf2/NF-E2) act as weak activators.","evidence":"Reporter assays on globin/GCSl promoters with multiple dimerization partners across cell lines","pmids":["12490281"],"confidence":"Medium","gaps":["Endogenous physiological targets not addressed","Context-dependence of activation vs repression not resolved"]},{"year":2002,"claim":"Linked MAFF expression to oxidative/electrophile stress, showing selective transcriptional induction by EpRE activators above other small Mafs.","evidence":"RT-PCR/Northern in HepG2 with actinomycin D transcription block","pmids":["11772409"],"confidence":"Medium","gaps":["Did not show MAFF protein function downstream of induction","tBHQ failure left requirement for sMaf upregulation ambiguous"]},{"year":2005,"claim":"Identified inflammatory cytokines as a MAFF-specific induction signal, separating MAFF from MAFG/MAFK regulation.","evidence":"RT-PCR time-course and Western blot in myometrial cells with actinomycin D","pmids":["16371591"],"confidence":"Medium","gaps":["Upstream transcription factor not yet identified","Downstream MAFF targets in this context not defined"]},{"year":2006,"claim":"Identified MIP as a coiled-coil interacting co-activator that confers transactivation onto an otherwise transactivation-deficient MAFF.","evidence":"Co-IP, in vitro binding, subcellular imaging, US2-reporter assay in HeLa; confirmed in a yeast reporter system in 2009","pmids":["16549056","19723544"],"confidence":"Medium","gaps":["Physiological relevance of MIP co-activation outside reporter systems unclear","Endogenous target genes of the MAFF-MIP pair not mapped"]},{"year":2016,"claim":"Consolidated the obligatory-partner model: small Mafs including MAFF are indispensable DNA-binding partners for CNC and Bach proteins, acting as activators or repressors by context.","evidence":"Review synthesizing genetic, structural, and biochemical data across labs","pmids":["27058431"],"confidence":"High","gaps":["Does not assign MAFF-specific endogenous targets","Partner-selection rules per cell type not specified"]},{"year":2019,"claim":"Provided the first direct endogenous target genes for MAFF, showing promoter occupancy and loss-of-function control of inflammatory cytokines CXCL1 and CSF3.","evidence":"siRNA knockdown, ChIP, RT-PCR, ELISA, paracrine co-culture","pmids":["30669188"],"confidence":"Medium","gaps":["Heterodimeric partner at these promoters not identified","Single cell system"]},{"year":2021,"claim":"Identified BACH1 as a key MAFF heterodimer partner and showed context-switching: BACH1-MAFF represses LDLR under inflammation but activates IL11 to drive STAT3-dependent metastasis under hypoxia.","evidence":"ChIP-seq, ChIP-MS, RNA-seq, knockdown/overexpression, KO mice, patient correlation; metastasis model and invasion assays","pmids":["33626882","34262028"],"confidence":"High","gaps":["What determines activator vs repressor outcome of BACH1-MAFF not mechanistically resolved","Cofactors distinguishing the two contexts unknown"]},{"year":2021,"claim":"Demonstrated MAFF acts as a host antiviral repressor of the HBV core promoter via competitive displacement of HNF-4α, and tied its induction to NF-κB downstream of IL-1β/TNF.","evidence":"siRNA screen with HBV reporter, CRISPR KO, ChIP, promoter mutagenesis, primary hepatocytes","pmids":["33980595"],"confidence":"High","gaps":["Whether MAFF binds HBV promoter as homodimer or heterodimer not defined","Generality across HBV genotypes untested"]},{"year":2021,"claim":"Showed MAFF is itself a regulated target, with miR-320a directly suppressing MAFF mRNA to control beta-cell ROS, proliferation, and survival.","evidence":"RIP-Seq, luciferase, Western, AAV8 beta-cell delivery, islet transplantation, hyperglycemic clamp","pmids":["34631276"],"confidence":"Medium","gaps":["Direct MAFF transcriptional targets in beta cells not mapped","Single lab"]},{"year":2024,"claim":"Established post-translational control of MAFF stability by BAP1 deubiquitination and linked stabilized MAFF to DUSP5-mediated ERK suppression in colorectal cancer.","evidence":"Quantitative proteomics, DUB library screen, Co-IP, ubiquitination assay, RNA-seq, xenografts","pmids":["39151323"],"confidence":"High","gaps":["Identity of the E3 ligase adding K48 chains unknown","Whether DUSP5 is a direct MAFF target not shown"]},{"year":2024,"claim":"Defined MAFF as a direct dual regulator of ferroptosis and cell cycle (repressing SLC7A11, controlling CDK6/CDKN2C) acting downstream of cAMP/PKA/CREB1 in therapy-stressed lung adenocarcinoma.","evidence":"CRISPR screens, scRNA-seq, ChIP-seq, RNA-seq, xenografts","pmids":["38266355"],"confidence":"High","gaps":["Heterodimeric partner at these promoters not defined","Balance between ferroptosis and cell-cycle effects per context unclear"]},{"year":2024,"claim":"Expanded MAFF's partner repertoire beyond CNC/Bach, showing BATF3 cooperation in repressing ZNF711 in ovarian cancer.","evidence":"Dual-luciferase, ChIP-PCR, Co-IP, immunofluorescence, siRNA, xenograft","pmids":["38908812"],"confidence":"Medium","gaps":["Whether BATF3 binds DNA jointly with MAFF or modulates it indirectly unresolved","Single lab"]},{"year":2025,"claim":"Linked HDAC6-mediated deacetylation to suppression of MAFF function, with MAFF directly repressing KLF5 to limit fibrosis and inflammation in lupus nephritis.","evidence":"ChIP, dual luciferase, overexpression/knockdown, MRL/lpr mouse model","pmids":["39412062"],"confidence":"Medium","gaps":["Acetylated MAFF residues not mapped","Direct vs indirect HDAC6 action on MAFF acetylation not fully resolved"]},{"year":2025,"claim":"Identified MAFF mRNA as an m6A/YTHDC1 client, defining a YTHDC1-MAFF-VMP1 axis protecting hepatocytes against oxidative stress in ischemia/reperfusion.","evidence":"YTHDC1/MAFF knockdown-overexpression with VMP1 rescue, in vitro H/R and in vivo I/R models","pmids":["40054588"],"confidence":"Medium","gaps":["m6A sites on MAFF mRNA not mapped","Whether VMP1 is a direct MAFF target not shown"]},{"year":2025,"claim":"Added a BACH1-MAFF activation node for CLCF1-STAT3 signaling protecting hepatocytes in ischemia-reperfusion injury, reinforcing partner-dependent activator function.","evidence":"CUT&Tag, RNA-seq, adenoviral overexpression in mice, hepatocyte assays","pmids":["40169936"],"confidence":"Medium","gaps":["Single lab","Contrast with BACH1-MAFF repressive contexts not reconciled"]},{"year":2025,"claim":"Implicated upstream factors controlling MAFF nuclear access (ZNF655) and a tumor-suppressive MAFF effect on YAP1 nuclear translocation, though mechanisms are incompletely defined.","evidence":"ZNF655 depletion with MAFF translocation imaging and CCND1 rescue; YAP1 localization by IF and overexpression with xenografts","pmids":["41088232","41287850"],"confidence":"Low","gaps":["Methodological detail for ZNF655-MAFF promoter binding incomplete","Mechanism of MAFF suppression of YAP1 translocation not defined","Apparently opposite oncogenic vs tumor-suppressive roles not reconciled"]},{"year":2026,"claim":"Defined MAFF as a master metabolic regulator of ferroptosis, directly remodeling iron-handling (SLC11A2, NCOA4) and lipid metabolism genes to tune ferroptosis susceptibility and tumor behavior.","evidence":"RNA-seq, ChIP-seq, ferroptosis and lipid metabolite assays, loss/gain-of-function in breast cancer","pmids":["42209456"],"confidence":"High","gaps":["Dimerization partner at these metabolic promoters not identified","How direction (pro- vs anti-ferroptotic) is set across tumor types unresolved"]},{"year":2026,"claim":"Extended MAFF's death-pathway control to necroptosis and divergent ferroptosis outcomes in pancreatic cancer via GATA4-MLKL repression and AKR1C1 activation.","evidence":"RNA-seq/GSEA with GATA4/MLKL knockdown and necroptosis inhibition; dual-luciferase for AKR1C1 with ferroptosis assays and xenografts","pmids":["42153582","41206944"],"confidence":"Medium","gaps":["Why MAFF promotes vs inhibits ferroptosis in different tumors unresolved","Single lab per axis"]},{"year":2026,"claim":"Confirmed the NRF2-MAFF heterodimer directly drives contraction-associated genes (PTGS2, OXTR) downstream of melatonin/MT2/PKC in myometrium, returning to MAFF's earliest reproductive context.","evidence":"Dual-luciferase, siRNA, PKC inhibition, collagen gel contraction, in vivo sow parturition","pmids":["41854048"],"confidence":"Medium","gaps":["Relative contribution of NRF2 vs MAFF to promoter occupancy not separated","Human relevance untested"]},{"year":null,"claim":"It remains unresolved what molecular rules determine whether a given MAFF dimer activates or represses a target, and which partner MAFF uses at each endogenous promoter across its many reported contexts.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or cofactor model explaining context-dependent activation vs repression","Partner identity unassigned at most ChIP-defined target promoters","Opposing oncogenic and tumor-suppressive roles not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,8,9,10,11,15,22,23]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,9,10,12,15,22]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[10,11,15,16,17,18,22,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,20]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,9,10,11,15,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,9,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15,22,23,24]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,22,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[15]}],"complexes":[],"partners":["BACH1","NRF2","BATF3","BAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULX9","full_name":"Transcription factor MafF","aliases":["U-Maf","V-maf musculoaponeurotic fibrosarcoma oncogene homolog F"],"length_aa":164,"mass_kda":17.8,"function":"Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (PubMed:8932385). However, they seem to serve as transcriptional activators by dimerizing with other (usually larger) basic-zipper proteins, such as NFE2L1/NRF1, and recruiting them to specific DNA-binding sites. Interacts with the upstream promoter region of the oxytocin receptor gene (PubMed:16549056, PubMed:8932385). May be a transcriptional enhancer in the up-regulation of the oxytocin receptor gene at parturition (PubMed:10527846)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9ULX9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAFF","classification":"Not Classified","n_dependent_lines":72,"n_total_lines":1208,"dependency_fraction":0.059602649006622516},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAFF","total_profiled":1310},"omim":[{"mim_id":"604877","title":"MAF bZIP TRANSCRIPTION FACTOR F; MAFF","url":"https://www.omim.org/entry/604877"},{"mim_id":"602020","title":"MAF bZIP TRANSCRIPTION FACTOR G; MAFG","url":"https://www.omim.org/entry/602020"},{"mim_id":"600197","title":"MAF bZIP TRANSCRIPTION FACTOR K; MAFK","url":"https://www.omim.org/entry/600197"},{"mim_id":"163260","title":"NUCLEAR FACTOR ERYTHROID 2-LIKE 1; NFE2L1","url":"https://www.omim.org/entry/163260"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAFF"},"hgnc":{"alias_symbol":["hMafF"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULX9","domains":[{"cath_id":"1.20.5.170","chopping":"18-125","consensus_level":"medium","plddt":94.5704,"start":18,"end":125}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX9-F1-predicted_aligned_error_v6.png","plddt_mean":81.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAFF","jax_strain_url":"https://www.jax.org/strain/search?query=MAFF"},"sequence":{"accession":"Q9ULX9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULX9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULX9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX9"}},"corpus_meta":[{"pmid":"27058431","id":"PMC_27058431","title":"Small Maf proteins (MafF, MafG, MafK): 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the Myometrial Contraction Through MT2-PKC-NRF2/MAFF Signaling Pathway in Sows.","date":"2026","source":"Journal of pineal research","url":"https://pubmed.ncbi.nlm.nih.gov/41854048","citation_count":0,"is_preprint":false},{"pmid":"42153582","id":"PMC_42153582","title":"MAFF Suppresses Necroptosis in Pancreatic Cancer via the GATA4-MLKL Axis.","date":"2026","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/42153582","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23318,"output_tokens":6754,"usd":0.085632,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15796,"output_tokens":6204,"usd":0.11704,"stage2_stop_reason":"end_turn"},"total_usd":0.202672,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"MafF encodes a small nuclear bZIP protein lacking the amino-terminal acidic transactivation domain present in c-Maf; when overexpressed via retroviral vector in CEF cells, MafF did not induce morphological transformation but induced colony formation in soft agar with very low efficiency; MafK protein was detected predominantly in nuclei by immunostaining.\",\n      \"method\": \"Retroviral overexpression in CEF cells, soft-agar colony assay, immunostaining with specific antibody, structural analysis of cDNA clones\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — retroviral OE with defined phenotypic readout and nuclear localization confirmed by antibody; single lab, two orthogonal methods\",\n      \"pmids\": [\"8361754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human MafF (hMafF) binds specifically to the US-2 element in the oxytocin receptor (OTR) gene promoter, as shown by yeast one-hybrid screening and electrophoretic mobility shift assay (EMSA); hMafF is an 18-kDa protein with a leucine zipper but no transactivation domain, preferentially expressed in term myometrium.\",\n      \"method\": \"Yeast one-hybrid screening of term myometrium cDNA library, EMSA, Northern hybridization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA-binding demonstrated by two orthogonal methods (yeast one-hybrid + EMSA); single lab\",\n      \"pmids\": [\"10527846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Murine MafF is dispensable for development: homozygous mafF null mice are born at normal Mendelian ratios with no obvious functional deficiencies, even in tissues where other small Maf proteins are low. The lacZ-knockin revealed prominent mafF expression in gut, lung, liver, heart outflow tract, cartilage, bone membrane, and skin, but not in hematopoietic cells at any developmental stage. mafF is regulated by three distinct promoters.\",\n      \"method\": \"Gene targeting (mafF null mice), lacZ knock-in reporter, developmental expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with Mendelian analysis, lacZ reporter for spatial expression, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"10409670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MafF can form homodimers and high-affinity heterodimers with CNC-bZip family members Nrf1, Nrf2, and NF-E2. MafF homodimers do not repress transcription (unlike MafG/MafK homodimers) on gamma-globin, beta-globin, and GCSl promoters in multiple cell lines, while MafF/CNC heterodimers act as weak transcriptional activators. MafF shows a specific regulatory role in combination with Jun at the GCSl promoter.\",\n      \"method\": \"Reporter gene assays in multiple cell lines, protein–protein interaction studies, promoter-reporter constructs\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with multiple promoters and dimerization partners; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"12490281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"mafF transcript is differentially induced by electrophile-response-element (EpRE) activators PDTC and PEITC (but not tBHQ) in HepG2 cells, and this induction is transcriptionally mediated; mafF is induced to a greater extent than mafG or mafK. The induction by tBHQ failure suggests that small Maf upregulation is not an absolute requirement for EpRE-mediated gene expression.\",\n      \"method\": \"RT-PCR/Northern blot in multiple cell lines, actinomycin D transcription inhibition assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcriptional induction confirmed by actinomycin D block; replicated across cell lines but no direct mechanistic dissection of MAFF protein function\",\n      \"pmids\": [\"11772409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAFF mRNA and protein are rapidly induced (within 30 min) by IL-1β and TNF in PHM1-31 myometrial cells at the transcriptional level (actinomycin D-sensitive); the highly homologous MAFG and MAFK transcripts and proteins are not modulated by these cytokines, indicating a cytokine-specific regulation unique to MAFF.\",\n      \"method\": \"RT-PCR time-course, actinomycin D inhibition, Western blot with MAFF-specific antiserum\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional induction confirmed by chemical inhibitor and protein-level validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"16371591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A novel protein MIP (MafF Interacting Protein) physically interacts with hMafF via its coiled-coil domain binding the leucine zipper of hMafF in vitro and in vivo; this interaction causes translocation of MIP from the cytoplasm to the nucleolus in HeLa cells. Co-expression of hMafF and MIP activates US2-element-driven transcription, whereas either alone has no effect, establishing MIP as a co-activator of hMafF.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro binding assay, subcellular localization imaging, promoter-reporter assay in HeLa cells\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding confirmed in vitro and in vivo, functional co-activation shown by reporter assay; single lab\",\n      \"pmids\": [\"16549056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Using a recombinant yeast detection system, MIP was confirmed to enable hMafF-dependent transactivation of US2-driven reporter (LacZ): only the co-presence of both MIP and hMafF activates the reporter, corroborating the co-activator role of MIP for hMafF.\",\n      \"method\": \"Recombinant yeast reporter system (beta-galactosidase quantitative assay), plasmid transformation of YM4271 yeast\",\n      \"journal\": \"Journal of microbiological methods\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method, confirmatory of prior finding in a heterologous system\",\n      \"pmids\": [\"19723544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"sMafs (MafF, MafG, MafK) are bZIP transcription factors that: (1) form homodimers that act as transcriptional repressors (lacking activation domain); (2) form obligatory heterodimers with CNC proteins (NF-E2 p45, Nrf1, Nrf2, Nrf3) and Bach proteins (Bach1, Bach2), which cannot bind DNA as monomers, making sMafs indispensable partners; (3) participate in transcriptional activation or repression depending on heterodimeric partner and context.\",\n      \"method\": \"Review synthesizing genetic analyses in mice, structural studies, and biochemical data across multiple labs\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — review consolidating independently replicated genetic and biochemical findings across multiple labs; established mechanistic framework\",\n      \"pmids\": [\"27058431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAFF directly binds the promoters of CXCL1 and CSF3 in PHM1-31 myometrial cells, as shown by ChIP, and MAFF knockdown significantly decreases CXCL1 and CSF3 transcript and protein levels. MAFF-dependent cytokine production in myometrial cells can modulate cytokine and matrix metalloproteinase gene expression in THP-1 monocytic cells in a paracrine manner.\",\n      \"method\": \"siRNA knockdown, ChIP, RT-PCR, ELISA, paracrine co-culture assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter occupancy by ChIP plus loss-of-function with transcript and protein readouts; single lab\",\n      \"pmids\": [\"30669188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAFF forms a heterodimer with BACH1 that directly binds the LDLR promoter MAF recognition element (MARE) under inflammatory conditions (LPS stimulation), transcriptionally downregulating LDLR expression. Under non-inflammatory conditions, MAFF positively correlates with LDLR. BACH1 assists MAFF in inflammatory contexts, as revealed by ChIP-mass spectrometry.\",\n      \"method\": \"ChIP-sequencing, ChIP-mass spectrometry, siRNA knockdown, overexpression in mouse and human liver cells, KO mouse experiments, correlation in 600 CAD patients\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-MS identified BACH1 as MAFF partner; ChIP-seq confirmed promoter binding; validated by KO and KD with in vitro and in vivo readouts across multiple systems\",\n      \"pmids\": [\"33626882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAFF heterodimerizes with BACH1 to directly activate IL11 transcription under hypoxic conditions in breast cancer cells; IL11 activates STAT3 signaling; inhibition of IL11 phenocopies MAFF inhibition in suppressing metastasis. MAFF expression is induced by hypoxia (HIF target).\",\n      \"method\": \"ChIP-sequencing, RNA-sequencing, siRNA knockdown, overexpression, invasion assay, metastasis mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — combined ChIP-seq and RNA-seq identified IL11 as direct target; functional rescue experiments confirmed pathway; multiple orthogonal methods\",\n      \"pmids\": [\"34262028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MafF suppresses transcription from the HBV core promoter by physically binding to the HBV core promoter region (ChIP analysis) and competitively inhibiting HNF-4α binding to an overlapping sequence in enhancer II (EnhII). MafF loss (via CRISPR or siRNA) increases HBV core RNA and pgRNA levels. MafF expression is induced by IL-1β or TNF-α in an NF-κB-dependent manner in hepatocytes.\",\n      \"method\": \"siRNA library screen with HBV/NanoLuc reporter, CRISPR/Cas9 KO, ChIP analysis, overexpression with promoter mutation, siRNA in primary hepatocytes\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding to viral promoter by ChIP, competitive inhibition with HNF-4α, loss-of-function by two methods (CRISPR + siRNA), promoter mutagenesis; multiple orthogonal experiments\",\n      \"pmids\": [\"33980595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-320a directly targets MafF mRNA (identified by RIP-Seq and confirmed by luciferase reporter assay), reducing MafF protein levels in pancreatic β cells; overexpression of miR-320a increases ROS, inhibits proliferation, and induces apoptosis of β cells, effects attributable to MafF suppression.\",\n      \"method\": \"RIP-Seq, luciferase reporter assay, Western blot, AAV8-mediated β cell-specific overexpression/inhibition, islet transplantation, hyperglycemic clamp\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-Seq + luciferase confirms direct miRNA targeting; in vivo validation in mice; single lab\",\n      \"pmids\": [\"34631276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAP1 (a nuclear deubiquitinating enzyme) binds to MAFF and deubiquitylates it, primarily removing K48-linked ubiquitin chains, thereby stabilizing MAFF protein. Stabilized MAFF upregulates DUSP5 expression, resulting in inhibition of ERK phosphorylation, which suppresses colorectal cancer cell growth.\",\n      \"method\": \"Quantitative proteomics, DUB expression library screening, Co-IP, ubiquitination assay, RNA sequencing, gain-of-function/loss-of-function in CRC cells and xenografts\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical deubiquitination assay, direct binding by Co-IP, downstream pathway defined by RNA-seq + phosphorylation readout, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"39151323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAFF directly regulates SLC7A11, CDK6, and CDKN2C transcription (by ChIP-seq), promoting ferroptosis (via SLC7A11 repression) and preventing cell cycle progression from G1 to S (via CDK6/CDKN2C). The cAMP/PKA/CREB1 pathway upregulates MAFF expression in response to cisplatin or ionizing radiation in LUAD.\",\n      \"method\": \"CRISPR screens (cell and murine models), single-cell RNA-seq, ChIP-seq, RNA-seq, cellular and xenograft models\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR functional screen + ChIP-seq identifies direct transcriptional targets; upstream pathway defined; validated in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"38266355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAFF binds to the ZNF711 promoter and, together with its interacting partner BATF3 (confirmed by co-IP and immunofluorescence co-localization), represses ZNF711 transcription; BATF3 knockdown alone or combined with MAFF knockdown produce similar effects on ZNF711 expression and apoptosis in ovarian cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP-PCR, Co-IP, immunofluorescence, siRNA knockdown, xenograft model\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and luciferase; BATF3 interaction confirmed by Co-IP and IF; single lab\",\n      \"pmids\": [\"38908812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC6 suppresses MAFF expression through deacetylation of MAFF, removing its inhibitory effect on KLF5 transcription; MAFF directly represses KLF5 promoter activity (confirmed by ChIP and dual luciferase assay). Loss of MAFF-mediated KLF5 repression enhances fibrosis and inflammatory response in lupus nephritis.\",\n      \"method\": \"ChIP, dual luciferase reporter assay, cell transfection (overexpression/knockdown), in vivo MRL/lpr mouse model, biochemical analyses\",\n      \"journal\": \"Renal failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms MAFF binding to KLF5 promoter; HDAC6-mediated deacetylation links to MAFF regulation; single lab\",\n      \"pmids\": [\"39412062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAFF heterodimerizes with BACH1 to directly transcriptionally activate CLCF1 (identified by CUT&Tag + RNA-seq), which subsequently triggers STAT3 signaling; MAFF overexpression reduces hepatocyte apoptosis and inflammation in hepatic ischemia-reperfusion injury in mice.\",\n      \"method\": \"CUT&Tag sequencing, RNA-seq, adenovirus-mediated overexpression in mice, in vitro hepatocyte assays\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag identifies direct CLCF1 target; BACH1 heterodimer established; downstream STAT3 pathway validated; single lab\",\n      \"pmids\": [\"40169936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDC1 (m6A reader) mediates nuclear export and stabilization of MAFF mRNA and promotes MAFF translation; MAFF in turn transcriptionally activates VMP1. In hepatocytes, the YTHDC1-MAFF-VMP1 axis protects against oxidative stress in hepatic ischemia/reperfusion injury.\",\n      \"method\": \"Knockdown/overexpression of YTHDC1 and MAFF, VMP1 functional rescue, in vitro H/R model, in vivo I/R mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiments establish pathway order; YTHDC1 role in MAFF mRNA stability/nuclear export defined; single lab\",\n      \"pmids\": [\"40054588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF655 promotes nuclear translocation of MAFF in ovarian cancer cells; nuclear MAFF then directly binds the CCND1 promoter and transcriptionally activates CCND1, promoting cell proliferation and stemness. Rescue experiments confirm CCND1 is required for ZNF655-dependent effects.\",\n      \"method\": \"ZNF655 depletion, MAFF nuclear translocation analysis (immunofluorescence), promoter binding (ChIP implied by 'direct binding'), rescue experiments, xenograft models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — nuclear translocation and promoter binding described but full methodological detail absent from abstract; single lab, single publication\",\n      \"pmids\": [\"41088232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAFF suppresses YAP1 nuclear translocation in NSCLC cells; MAFF overexpression reduces YAP1, VEGF, and CTGF expression and inhibits angiogenesis both in vitro and in nude mouse xenograft models.\",\n      \"method\": \"Western blot, immunofluorescence (YAP1 localization), overexpression experiments, xenograft mouse model, IHC of clinical samples\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — YAP1 nuclear translocation suppression by IF established, but mechanism of how MAFF suppresses YAP1 translocation not defined; single lab\",\n      \"pmids\": [\"41287850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MAFF directly transcriptionally activates SLC11A2 and NCOA4 (expanding the labile iron pool) and represses CPT2, FASN, and SCD1 (shifting lipid metabolism toward PUFAs), as established by combined RNA-seq and ChIP-seq; these metabolic changes promote ferroptosis susceptibility and tumor invasion in breast cancer cells.\",\n      \"method\": \"RNA-sequencing, ChIP-sequencing, functional ferroptosis assays, lipid metabolite measurement, loss-of-function/gain-of-function experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq + RNA-seq identifies direct transcriptional targets; mechanistic consequences (iron pool, lipid peroxidation) validated by metabolite and cell death assays; multiple orthogonal methods\",\n      \"pmids\": [\"42209456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MAFF acts as a direct transcriptional repressor of GATA4; GATA4 in turn transcriptionally activates MLKL (necroptotic executioner). MAFF depletion reactivates the GATA4-MLKL axis, triggering necroptosis in pancreatic cancer cells. Pharmacological inhibition of necroptosis or knockdown of GATA4/MLKL reverses the growth-inhibitory effects of MAFF silencing.\",\n      \"method\": \"RNA-sequencing, GSEA, MAFF KO/overexpression, genetic knockdown of GATA4 and MLKL, pharmacological necroptosis inhibition, in vivo tumor models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis established by double-KD rescue; pathway defined by RNA-seq + GSEA; single lab\",\n      \"pmids\": [\"42153582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MAFF directly binds the promoter of AKR1C1 and transcriptionally activates it (confirmed by dual-luciferase reporter assay); the MAFF-AKR1C1 axis leads to MDA accumulation and elevated lipid ROS, inhibiting ferroptosis and promoting pancreatic cancer progression.\",\n      \"method\": \"Dual-luciferase reporter assay, bioinformatics (ELMER), in vitro cellular assays, xenograft models, transcriptome sequencing\",\n      \"journal\": \"QJM\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by luciferase assay; ferroptotic consequences validated in vitro and in vivo; single lab\",\n      \"pmids\": [\"41206944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In sow myometrium, NRF2 and MAFF directly target the promoters of PTGS2 and OXTR (contraction-associated genes), confirmed by dual-luciferase reporter assays; melatonin acting through the MT2 receptor activates PKC, which regulates NRF2 and MAFF expression to enhance myometrial contractility. Silencing MAFF in melatonin-treated cells reduces contraction-associated protein expression.\",\n      \"method\": \"Dual-luciferase reporter assay, siRNA knockdown, PKC pathway inhibition, collagen gel contraction assay, in vivo sow parturition experiments\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct MAFF promoter binding on PTGS2 and OXTR confirmed by luciferase assay; upstream pathway (MT2-PKC) defined; single lab\",\n      \"pmids\": [\"41854048\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAFF is a small bZIP transcription factor that lacks an intrinsic transactivation domain and functions as an obligatory heterodimeric partner for CNC-family (Nrf1, Nrf2, NF-E2) and Bach-family (Bach1, Bach2) proteins, which cannot bind DNA alone; MAFF homodimers act as transcriptional repressors, while heterodimers activate or repress target genes (including LDLR, IL11, CLCF1, CXCL1, CSF3, SLC7A11, CDK6, AKR1C1, GATA4, SLC11A2, and NCOA4) depending on partner and cellular context; MAFF protein stability is regulated by K48-linked ubiquitination and deubiquitination by BAP1, its mRNA is stabilized and exported by the m6A reader YTHDC1, its expression is rapidly induced transcriptionally by IL-1β/TNF via NF-κB, and it is post-translationally suppressed by HDAC6-mediated deacetylation, collectively positioning MAFF as a context-dependent transcriptional switch linking inflammatory signaling, iron/lipid metabolism, ferroptosis, and cell cycle regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAFF is a small nuclear bZIP transcription factor that lacks an intrinsic transactivation domain and functions as a context-dependent transcriptional switch coordinating inflammatory, metabolic, and cell-fate programs [#0, #8]. It dimerizes through its leucine zipper: homodimers are transcriptionally inert or repressive, whereas obligatory heterodimers with CNC-family proteins (Nrf1, Nrf2, NF-E2) and Bach-family proteins (Bach1, Bach2)\\u2014which cannot bind DNA alone\\u2014activate or repress target genes at MAF recognition elements depending on partner and cellular context [#3, #8]. Through BACH1 heterodimers, MAFF directly binds promoters to repress LDLR under inflammation [#10] and to activate IL11 and CLCF1, both feeding STAT3 signaling in cancer and liver injury [#11, #18], while NRF2 partnership drives contraction-associated genes PTGS2 and OXTR in myometrium [#25]. MAFF directly controls a broad transcriptional program governing ferroptosis and lipid/iron metabolism\\u2014repressing SLC7A11 and activating SLC11A2, NCOA4, and AKR1C1 while reprogramming lipid metabolism enzymes [#15, #22, #24]\\u2014and cell-cycle and death pathways via CDK6/CDKN2C, GATA4-MLKL necroptosis, and DUSP5-mediated ERK suppression [#14, #15, #23]. MAFF expression and stability are heavily regulated: it is rapidly and transcriptionally induced by IL-1\\u03b2/TNF through NF-\\u03baB [#5, #12], its mRNA is exported and stabilized by the m6A reader YTHDC1 [#19], and its protein is stabilized by BAP1-mediated removal of K48-linked ubiquitin and suppressed by HDAC6-mediated deacetylation [#14, #17]. Loss-of-function in mice shows MAFF is dispensable for development [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established MAFF as a small bZIP protein lacking the acidic transactivation domain of large Mafs, raising the question of how it could regulate transcription at all.\",\n      \"evidence\": \"Retroviral overexpression in CEF cells with soft-agar assay and structural analysis of cDNA, nuclear localization by immunostaining\",\n      \"pmids\": [\"8361754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No DNA target or dimerization partner identified\", \"Weak transformation phenotype not mechanistically explained\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed MAFF binds a defined promoter element (US-2 of the oxytocin receptor gene) and is enriched in term myometrium, giving the protein a concrete DNA-binding target.\",\n      \"evidence\": \"Yeast one-hybrid screening of myometrium cDNA library, EMSA, Northern hybridization\",\n      \"pmids\": [\"10527846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether binding required a heterodimeric partner\", \"No functional transcriptional readout in cells\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Genetic deletion in mice resolved whether MAFF is individually essential, showing it is dispensable for development while mapping its broad tissue expression via three promoters.\",\n      \"evidence\": \"MafF null mice with Mendelian analysis and lacZ knock-in reporter\",\n      \"pmids\": [\"10409670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with MafG/MafK not directly tested here\", \"No molecular target defined in vivo\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined MAFF's dimerization logic, distinguishing it from other small Mafs: its homodimers are not repressive, while CNC heterodimers (Nrf1/Nrf2/NF-E2) act as weak activators.\",\n      \"evidence\": \"Reporter assays on globin/GCSl promoters with multiple dimerization partners across cell lines\",\n      \"pmids\": [\"12490281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous physiological targets not addressed\", \"Context-dependence of activation vs repression not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked MAFF expression to oxidative/electrophile stress, showing selective transcriptional induction by EpRE activators above other small Mafs.\",\n      \"evidence\": \"RT-PCR/Northern in HepG2 with actinomycin D transcription block\",\n      \"pmids\": [\"11772409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not show MAFF protein function downstream of induction\", \"tBHQ failure left requirement for sMaf upregulation ambiguous\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified inflammatory cytokines as a MAFF-specific induction signal, separating MAFF from MAFG/MAFK regulation.\",\n      \"evidence\": \"RT-PCR time-course and Western blot in myometrial cells with actinomycin D\",\n      \"pmids\": [\"16371591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream transcription factor not yet identified\", \"Downstream MAFF targets in this context not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified MIP as a coiled-coil interacting co-activator that confers transactivation onto an otherwise transactivation-deficient MAFF.\",\n      \"evidence\": \"Co-IP, in vitro binding, subcellular imaging, US2-reporter assay in HeLa; confirmed in a yeast reporter system in 2009\",\n      \"pmids\": [\"16549056\", \"19723544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of MIP co-activation outside reporter systems unclear\", \"Endogenous target genes of the MAFF-MIP pair not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Consolidated the obligatory-partner model: small Mafs including MAFF are indispensable DNA-binding partners for CNC and Bach proteins, acting as activators or repressors by context.\",\n      \"evidence\": \"Review synthesizing genetic, structural, and biochemical data across labs\",\n      \"pmids\": [\"27058431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not assign MAFF-specific endogenous targets\", \"Partner-selection rules per cell type not specified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the first direct endogenous target genes for MAFF, showing promoter occupancy and loss-of-function control of inflammatory cytokines CXCL1 and CSF3.\",\n      \"evidence\": \"siRNA knockdown, ChIP, RT-PCR, ELISA, paracrine co-culture\",\n      \"pmids\": [\"30669188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterodimeric partner at these promoters not identified\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified BACH1 as a key MAFF heterodimer partner and showed context-switching: BACH1-MAFF represses LDLR under inflammation but activates IL11 to drive STAT3-dependent metastasis under hypoxia.\",\n      \"evidence\": \"ChIP-seq, ChIP-MS, RNA-seq, knockdown/overexpression, KO mice, patient correlation; metastasis model and invasion assays\",\n      \"pmids\": [\"33626882\", \"34262028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines activator vs repressor outcome of BACH1-MAFF not mechanistically resolved\", \"Cofactors distinguishing the two contexts unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated MAFF acts as a host antiviral repressor of the HBV core promoter via competitive displacement of HNF-4\\u03b1, and tied its induction to NF-\\u03baB downstream of IL-1\\u03b2/TNF.\",\n      \"evidence\": \"siRNA screen with HBV reporter, CRISPR KO, ChIP, promoter mutagenesis, primary hepatocytes\",\n      \"pmids\": [\"33980595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAFF binds HBV promoter as homodimer or heterodimer not defined\", \"Generality across HBV genotypes untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed MAFF is itself a regulated target, with miR-320a directly suppressing MAFF mRNA to control beta-cell ROS, proliferation, and survival.\",\n      \"evidence\": \"RIP-Seq, luciferase, Western, AAV8 beta-cell delivery, islet transplantation, hyperglycemic clamp\",\n      \"pmids\": [\"34631276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MAFF transcriptional targets in beta cells not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established post-translational control of MAFF stability by BAP1 deubiquitination and linked stabilized MAFF to DUSP5-mediated ERK suppression in colorectal cancer.\",\n      \"evidence\": \"Quantitative proteomics, DUB library screen, Co-IP, ubiquitination assay, RNA-seq, xenografts\",\n      \"pmids\": [\"39151323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ligase adding K48 chains unknown\", \"Whether DUSP5 is a direct MAFF target not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined MAFF as a direct dual regulator of ferroptosis and cell cycle (repressing SLC7A11, controlling CDK6/CDKN2C) acting downstream of cAMP/PKA/CREB1 in therapy-stressed lung adenocarcinoma.\",\n      \"evidence\": \"CRISPR screens, scRNA-seq, ChIP-seq, RNA-seq, xenografts\",\n      \"pmids\": [\"38266355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterodimeric partner at these promoters not defined\", \"Balance between ferroptosis and cell-cycle effects per context unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded MAFF's partner repertoire beyond CNC/Bach, showing BATF3 cooperation in repressing ZNF711 in ovarian cancer.\",\n      \"evidence\": \"Dual-luciferase, ChIP-PCR, Co-IP, immunofluorescence, siRNA, xenograft\",\n      \"pmids\": [\"38908812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BATF3 binds DNA jointly with MAFF or modulates it indirectly unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked HDAC6-mediated deacetylation to suppression of MAFF function, with MAFF directly repressing KLF5 to limit fibrosis and inflammation in lupus nephritis.\",\n      \"evidence\": \"ChIP, dual luciferase, overexpression/knockdown, MRL/lpr mouse model\",\n      \"pmids\": [\"39412062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylated MAFF residues not mapped\", \"Direct vs indirect HDAC6 action on MAFF acetylation not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified MAFF mRNA as an m6A/YTHDC1 client, defining a YTHDC1-MAFF-VMP1 axis protecting hepatocytes against oxidative stress in ischemia/reperfusion.\",\n      \"evidence\": \"YTHDC1/MAFF knockdown-overexpression with VMP1 rescue, in vitro H/R and in vivo I/R models\",\n      \"pmids\": [\"40054588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A sites on MAFF mRNA not mapped\", \"Whether VMP1 is a direct MAFF target not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a BACH1-MAFF activation node for CLCF1-STAT3 signaling protecting hepatocytes in ischemia-reperfusion injury, reinforcing partner-dependent activator function.\",\n      \"evidence\": \"CUT&Tag, RNA-seq, adenoviral overexpression in mice, hepatocyte assays\",\n      \"pmids\": [\"40169936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Contrast with BACH1-MAFF repressive contexts not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated upstream factors controlling MAFF nuclear access (ZNF655) and a tumor-suppressive MAFF effect on YAP1 nuclear translocation, though mechanisms are incompletely defined.\",\n      \"evidence\": \"ZNF655 depletion with MAFF translocation imaging and CCND1 rescue; YAP1 localization by IF and overexpression with xenografts\",\n      \"pmids\": [\"41088232\", \"41287850\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Methodological detail for ZNF655-MAFF promoter binding incomplete\", \"Mechanism of MAFF suppression of YAP1 translocation not defined\", \"Apparently opposite oncogenic vs tumor-suppressive roles not reconciled\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined MAFF as a master metabolic regulator of ferroptosis, directly remodeling iron-handling (SLC11A2, NCOA4) and lipid metabolism genes to tune ferroptosis susceptibility and tumor behavior.\",\n      \"evidence\": \"RNA-seq, ChIP-seq, ferroptosis and lipid metabolite assays, loss/gain-of-function in breast cancer\",\n      \"pmids\": [\"42209456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dimerization partner at these metabolic promoters not identified\", \"How direction (pro- vs anti-ferroptotic) is set across tumor types unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended MAFF's death-pathway control to necroptosis and divergent ferroptosis outcomes in pancreatic cancer via GATA4-MLKL repression and AKR1C1 activation.\",\n      \"evidence\": \"RNA-seq/GSEA with GATA4/MLKL knockdown and necroptosis inhibition; dual-luciferase for AKR1C1 with ferroptosis assays and xenografts\",\n      \"pmids\": [\"42153582\", \"41206944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why MAFF promotes vs inhibits ferroptosis in different tumors unresolved\", \"Single lab per axis\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed the NRF2-MAFF heterodimer directly drives contraction-associated genes (PTGS2, OXTR) downstream of melatonin/MT2/PKC in myometrium, returning to MAFF's earliest reproductive context.\",\n      \"evidence\": \"Dual-luciferase, siRNA, PKC inhibition, collagen gel contraction, in vivo sow parturition\",\n      \"pmids\": [\"41854048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of NRF2 vs MAFF to promoter occupancy not separated\", \"Human relevance untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular rules determine whether a given MAFF dimer activates or represses a target, and which partner MAFF uses at each endogenous promoter across its many reported contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or cofactor model explaining context-dependent activation vs repression\", \"Partner identity unassigned at most ChIP-defined target promoters\", \"Opposing oncogenic and tumor-suppressive roles not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 8, 9, 10, 11, 15, 22, 23]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 9, 10, 12, 15, 22]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [10, 11, 15, 16, 17, 18, 22, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 9, 10, 11, 15, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 9, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 22, 23, 24]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 22, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BACH1\", \"NRF2\", \"BATF3\", \"BAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}