{"gene":"MAFF","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1993,"finding":"MafF is a nuclear bZIP protein that lacks a transcriptional activation domain (N-terminal acidic domain), localizes to the nucleus, and does not induce morphological transformation of chicken embryo fibroblasts but can weakly induce colony formation in soft agar when overexpressed via retroviral vector.","method":"Structural analysis, retroviral overexpression, immunofluorescence, soft agar colony assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and functional assay in cells, single lab","pmids":["8361754"],"is_preprint":false},{"year":1999,"finding":"Human MafF (hMafF) binds specifically to the US-2 DNA element in the oxytocin receptor (OTR) gene promoter, as demonstrated by electrophoretic mobility shift assay, and its protein is preferentially expressed in term myometrium, supporting a role in OTR gene upregulation at parturition.","method":"Yeast one-hybrid screen, EMSA, Northern/Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct DNA-binding assay with EMSA, single lab","pmids":["10527846"],"is_preprint":false},{"year":1999,"finding":"MafF is dispensable for normal development in mice: homozygous mafF null mutant mice are born in normal Mendelian ratios with no obvious functional deficiencies, and lacZ knock-in reveals prominent expression in gut, lung, liver, outflow tract of heart, cartilage, bone membrane, and skin but not in hematopoietic cells.","method":"Gene targeting (knockout), lacZ reporter knock-in, developmental expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function mouse model with defined phenotypic readout, replicated tissue expression","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 on gamma-globin, beta-globin, or GCS1 promoters in multiple cell lines, whereas MafF/CNC heterodimers act as weak transcriptional activators; in combination with Jun on the GCS1 promoter, MafF shows a specific regulatory role.","method":"Co-immunoprecipitation, promoter-reporter assays, overexpression in multiple cell lines","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction and functional reporter assays, multiple promoters tested","pmids":["12490281"],"is_preprint":false},{"year":2002,"finding":"mafF mRNA expression is induced to the greatest extent among the three small Maf genes by electrophile response element (EpRE) activators PDTC and PEITC (but not tBHQ) in HepG2 cells, and this induction is transcriptionally mediated, indicating mafF is a stress-responsive gene regulated via mechanisms distinct from mafG and mafK.","method":"Northern/RT-PCR, actinomycin D transcription block, multiple cell lines","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 — mRNA induction assays in multiple lines, transcriptional mechanism confirmed by actinomycin D","pmids":["11772409"],"is_preprint":false},{"year":2005,"finding":"MAFF transcript and protein levels are rapidly induced (within 30 min) by proinflammatory cytokines IL-1β and TNF in PHM1-31 myometrial cells at the transcriptional level (blocked by actinomycin D); this induction is specific to MAFF and not shared by MAFG or MAFK.","method":"RT-PCR, Western blot with MAFF-specific antiserum, actinomycin D block, time-course experiments","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — protein-level confirmation, actinomycin D mechanistic validation, specificity shown for MAFF vs paralogs","pmids":["16371591"],"is_preprint":false},{"year":2006,"finding":"A novel protein MIP (MafF interacting protein) interacts with hMafF via its coiled-coil domain binding to the leucine zipper of hMafF; this interaction causes MIP to translocate from the cytoplasm to the nucleolus; co-expression of MIP and hMafF (but not either alone) activates transcription from a promoter containing US2 elements.","method":"In vitro pull-down, co-immunoprecipitation, subcellular localization by fluorescence microscopy, promoter-reporter assay, domain truncation","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo interaction with domain mapping and functional reporter readout","pmids":["16549056"],"is_preprint":false},{"year":2016,"finding":"Small Maf proteins including MafF form homodimers (acting as transcriptional repressors lacking activation domain) and heterodimers with CNC proteins (p45 NF-E2, Nrf1, Nrf2, Nrf3) and Bach proteins (Bach1, Bach2); CNC and Bach proteins cannot bind DNA as monomers and require sMaf as obligatory partners; heterodimer function (activation or repression) depends on the partner.","method":"Review integrating prior biochemical, genetic, and structural data from multiple labs","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1–2 — extensively replicated across labs with biochemical, genetic, and structural validation","pmids":["27058431"],"is_preprint":false},{"year":2019,"finding":"MAFF directly binds to the CXCL1 and CSF3 gene promoters and is required for their transcriptional activation in myometrial cells; MAFF knockdown significantly reduces CXCL1 and CSF3 transcript and protein levels, and MAFF-dependent signaling in myometrial cells can regulate cytokine and matrix metalloproteinase expression in THP-1 monocytic cells in a paracrine fashion.","method":"siRNA knockdown, chromatin immunoprecipitation (ChIP), RT-qPCR, protein measurements, paracrine co-culture assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct binding, loss-of-function confirms transcriptional dependency","pmids":["30669188"],"is_preprint":false},{"year":2021,"finding":"MAFF forms a heterodimer with BACH1 that directly targets and transcriptionally activates the IL11 gene promoter in hypoxic breast cancer cells; IL11 activation leads to downstream STAT3 signaling to promote tumor invasion and metastasis; MAFF expression is induced by HIF under hypoxia.","method":"ChIP-seq, RNA-seq, siRNA knockdown, overexpression, invasion assays, in vivo metastasis models, IL11 inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq + RNA-seq + functional rescue with multiple orthogonal methods including in vivo","pmids":["34262028"],"is_preprint":false},{"year":2021,"finding":"MAFF transcription is activated by a circRNA (cia-MAF) that binds to the MAFF promoter and recruits the TIP60 histone acetyltransferase complex; loss of cia-MAF reduces TIP60 complex binding at the MAFF promoter and decreases MAFF expression, impacting liver tumor-initiating cell self-renewal and metastasis.","method":"circRNA knockout (CRISPR), promoter binding assays, ChIP for TIP60 complex, overexpression, xenograft models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with defined mechanistic readout, ChIP confirms TIP60 recruitment","pmids":["34403373"],"is_preprint":false},{"year":2021,"finding":"In hepatocellular carcinoma, MafF is a direct target of miR-224-5p; circular RNA circ-ITCH sponges miR-224-5p to stabilize MafF expression; MafF overexpression inhibits HCC cell proliferation and induces apoptosis, acting as a tumor suppressor.","method":"Luciferase reporter assay, RNA pull-down assay, lentiviral overexpression, rescue experiments, proliferation and apoptosis assays","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 — direct miRNA target validation with luciferase assay plus RNA pull-down and rescue","pmids":["31969212"],"is_preprint":false},{"year":2021,"finding":"MafF suppresses transcription from the HBV core promoter by physically binding to the promoter and competitively inhibiting HNF-4α binding to an overlapping sequence in enhancer II (EnhII); MafF expression is induced by IL-1β or TNF-α in an NF-κB-dependent manner.","method":"siRNA knockdown, CRISPR/Cas9 knockout, ChIP, overexpression with mutant binding site, HBV reporter virus, NF-κB inhibition","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP direct binding, competitive inhibition shown by binding-site mutation, CRISPR KO, multiple cell models","pmids":["33980595"],"is_preprint":false},{"year":2021,"finding":"MAFF positively correlates with LDLR expression in non-inflammatory conditions but, upon LPS stimulation, forms heterodimers with BACH1 that bind the MAF recognition element (MARE) in the LDLR promoter to transcriptionally downregulate LDLR expression; BACH1 is identified as MAFF's partner under inflammatory conditions by ChIP-mass spectrometry.","method":"ChIP-seq, ChIP-mass spectrometry (ChIP-MS), siRNA knockdown, overexpression, in vivo mouse experiments, human patient correlation","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-MS for partner identification, ChIP-seq for binding site, in vitro and in vivo validation","pmids":["33626882"],"is_preprint":false},{"year":2021,"finding":"miR-320a directly targets MafF mRNA (validated by RIP-Seq and luciferase reporter assay); overexpression of miR-320a inhibits MafF protein expression, increases ROS, inhibits β-cell proliferation, and induces apoptosis, causing pancreatic β-cell dysfunction.","method":"RIP-Seq, luciferase reporter assay, Western blotting, AAV8-mediated β-cell specific overexpression/inhibition, islet transplantation, hyperglycemic clamp","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 — direct target validation by luciferase and RIP-Seq, in vivo AAV model with functional readout","pmids":["34631276"],"is_preprint":false},{"year":2024,"finding":"BAP1, a nuclear deubiquitinating enzyme, binds to MAFF and removes K48-linked ubiquitin chains, stabilizing MAFF protein; stabilized MAFF upregulates DUSP5 expression, resulting in inhibition of ERK phosphorylation and suppression of colorectal cancer growth.","method":"Quantitative proteomics, Co-IP, DUB library screen, ubiquitination assays (K48-specific), MAFF overexpression/knockdown, in vitro and xenograft models, RNA-seq","journal":"European journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical deubiquitination assay, K48-ubiquitin specificity, functional rescue with downstream pathway validation","pmids":["39151323"],"is_preprint":false},{"year":2024,"finding":"MAFF directly binds to the ZNF711 promoter and represses its transcription; MAFF also interacts with BATF3 (demonstrated by co-immunoprecipitation and co-localization), and BATF3 similarly binds the ZNF711 promoter; simultaneous knockdown of BATF3 and MAFF phenocopies single knockdowns on ZNF711 transcription and apoptosis, indicating MAFF-BATF3 heterodimer represses ZNF711.","method":"Dual luciferase assay, ChIP-PCR, Co-IP, immunofluorescence, knockdown rescue experiments","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding confirmed by ChIP, protein interaction by Co-IP, epistasis by double knockdown","pmids":["38908812"],"is_preprint":false},{"year":2024,"finding":"MAFF regulates ferroptosis and cell cycle progression in lung adenocarcinoma by directly controlling transcription of SLC7A11, CDK6, and CDKN2C (identified by ChIP-seq and RNA-seq); MAFF loss promotes cell cycle G1-to-S progression and reduces ferroptosis sensitivity; the cAMP/PKA/CREB1 intracellular pathway upregulates MAFF expression in response to cisplatin or ionizing radiation.","method":"CRISPR screens, ChIP-seq, RNA-seq, single-cell RNA-seq, xenograft models, pharmacological cAMP/PKA pathway analysis","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 1–2 — CRISPR loss-of-function, ChIP-seq binding evidence, multiple orthogonal methods in cell and animal models","pmids":["38266355"],"is_preprint":false},{"year":2025,"finding":"MAFF and BACH1 form a heterodimer that directly binds to the CLCF1 gene promoter (identified by CUT&Tag and RNA-seq) to transcriptionally activate CLCF1, which subsequently activates STAT3 signaling to protect against hepatic ischemia-reperfusion injury by reducing apoptosis and inflammation.","method":"CUT&Tag, RNA-seq, adenovirus-mediated overexpression, mouse I/R model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — CUT&Tag for direct binding, in vivo model, single lab","pmids":["40169936"],"is_preprint":false},{"year":2025,"finding":"YTHDC1 (an m6A reader) promotes nuclear export and stability of MAFF mRNA, enhancing MAFF translation; MAFF in turn transcriptionally activates VMP1, protecting hepatocytes from oxidative stress in ischemia/reperfusion injury.","method":"Knockdown/overexpression of YTHDC1 and MAFF, VMP1 rescue experiments, mouse I/R model, mechanistic mRNA stability/export assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis rescue experiments and defined molecular pathway, single lab","pmids":["40054588"],"is_preprint":false},{"year":2025,"finding":"ZNF655 promotes nuclear translocation of MAFF in ovarian cancer cells; nuclear MAFF directly binds the CCND1 promoter and activates its transcription, driving proliferation and stemness; MAFF knockdown phenocopies ZNF655 depletion.","method":"Co-IP, ChIP, reporter assay, knockdown/overexpression, xenograft models","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct promoter binding, nuclear translocation assay, rescue experiments","pmids":["41088232"],"is_preprint":false},{"year":2025,"finding":"MAFF suppresses nuclear translocation of YAP1 in non-small cell lung cancer cells, reducing downstream VEGF and CTGF expression and inhibiting angiogenesis; MAFF overexpression reduces tumor growth and microvessel density in vivo.","method":"Western blot, immunofluorescence, overexpression, xenograft models, IHC for microvessel density","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization assay (IF for YAP1 nuclear translocation), in vivo xenograft validation","pmids":["41287850"],"is_preprint":false},{"year":2025,"finding":"HDAC6 deacetylates MAFF to suppress its expression; loss of MAFF derepresses KLF5 transcription (MAFF directly suppresses KLF5 promoter activity as shown by ChIP and dual luciferase reporter assay), thereby enhancing renal fibrosis and inflammation in lupus nephritis.","method":"ChIP, dual luciferase reporter assay, HDAC6 inhibition, overexpression/knockdown, in vitro and MRL/lpr mouse model","journal":"Renal failure","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding by ChIP and luciferase, deacetylation mechanism, in vivo model","pmids":["39412062"],"is_preprint":false},{"year":2025,"finding":"NRF2 and MAFF directly target the promoters of contraction-associated protein genes PTGS2 and OXTR (confirmed by dual-luciferase reporter assay) downstream of melatonin-MT2 receptor-PKC signaling; silencing NRF2 or MAFF reduces contraction-associated protein expression and attenuates myometrial contractility.","method":"Dual-luciferase reporter assay, siRNA knockdown, collagen gel contraction assay, pharmacological receptor and kinase inhibition","journal":"Journal of pineal research","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter targeting validated by luciferase, epistasis confirmed by siRNA, functional contraction readout","pmids":["41854048"],"is_preprint":false},{"year":2025,"finding":"MAFF directly binds the AKR1C1 promoter (confirmed by dual-luciferase reporter assay) and transcriptionally activates AKR1C1; the MAFF-AKR1C1 axis inhibits ferroptosis by reducing MDA accumulation and lipid ROS, thereby promoting pancreatic cancer progression.","method":"Dual-luciferase reporter assay, MAFF knockdown in cell lines, xenograft models, transcriptome sequencing","journal":"QJM : monthly journal of the Association of Physicians","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcriptional target validation by luciferase, in vivo xenograft, defined ferroptosis mechanism","pmids":["41206944"],"is_preprint":false}],"current_model":"MAFF is a nuclear bZIP transcription factor that lacks an intrinsic transactivation domain and functions as an obligatory heterodimeric partner for CNC (Nrf1, Nrf2, NF-E2) and Bach (Bach1, Bach2) proteins, which cannot bind DNA alone; MAFF homodimers act as transcriptional repressors, while its heterodimers can activate or repress target genes (including IL11, LDLR, CLCF1, CXCL1, CSF3, SLC7A11, CDK6, AKR1C1, CCND1, and viral promoters) in a context- and partner-dependent manner; MAFF protein stability is regulated by BAP1-mediated deubiquitination (K48-ubiquitin) and HDAC6-mediated deacetylation, its mRNA is stabilized and exported by the m6A reader YTHDC1 and sponged by circRNAs, its expression is transcriptionally induced by proinflammatory cytokines (IL-1β, TNF) via NF-κB and by HIF under hypoxia, and its nuclear localization can be promoted by ZNF655, enabling it to regulate downstream pathways including STAT3, ERK, YAP1, and ferroptosis in diverse biological contexts."},"narrative":{"teleology":[{"year":1993,"claim":"Identification of MafF as a nuclear bZIP protein lacking a transactivation domain established its structural distinction from large Maf oncoproteins and predicted that it would function through heterodimerization rather than autonomous transcriptional activation.","evidence":"Retroviral overexpression, immunofluorescence localization, and transformation assays in chicken embryo fibroblasts","pmids":["8361754"],"confidence":"Medium","gaps":["No heterodimeric partners identified at this stage","Weak soft-agar colony formation not independently replicated","DNA-binding specificity not defined"]},{"year":1999,"claim":"Demonstration that MAFF binds the OTR promoter US-2 element and that mafF-null mice develop normally established MAFF as a sequence-specific DNA-binding factor with functional redundancy among small Maf paralogs.","evidence":"EMSA for DNA binding; gene-targeted mafF knockout mice with lacZ knock-in for expression mapping","pmids":["10527846","10409670"],"confidence":"High","gaps":["Compound small Maf knockouts not yet tested","Functional consequence of OTR promoter binding in vivo not demonstrated"]},{"year":2002,"claim":"Biochemical demonstration that MafF forms homodimers (repressive) and heterodimers with CNC proteins (activating) on globin and antioxidant promoters defined its dual role as a molecular switch for transcriptional regulation, and identification of electrophile-responsive MAFF induction established it as a stress-responsive gene.","evidence":"Co-immunoprecipitation, promoter-reporter assays on multiple promoters; Northern blot with actinomycin D block in HepG2 cells","pmids":["12490281","11772409"],"confidence":"Medium","gaps":["In vivo relevance of homodimer repression not tested","Whether MafF and MafG/MafK heterodimers differ in target specificity unresolved"]},{"year":2005,"claim":"Rapid induction of MAFF (but not MAFG/MAFK) by IL-1β and TNF at the transcriptional level revealed MAFF as a uniquely inflammatory-responsive small Maf member, linking it to NF-κB-driven gene programs.","evidence":"RT-PCR and Western blot with actinomycin D block in myometrial cells; paralog specificity confirmed","pmids":["16371591"],"confidence":"Medium","gaps":["NF-κB binding to MAFF promoter not directly shown at this point","Downstream inflammatory targets of MAFF not yet identified"]},{"year":2016,"claim":"Consolidation across multiple labs confirmed that small Mafs including MAFF are obligatory partners for CNC (Nrf1–3, NF-E2) and Bach (Bach1, Bach2) proteins, which cannot bind DNA as monomers, establishing the general paradigm for MAFF-dependent transcriptional control.","evidence":"Integrative review of biochemical, genetic, and structural data from multiple independent laboratories","pmids":["27058431"],"confidence":"High","gaps":["Structural basis for partner selectivity among small Mafs not resolved","Genome-wide binding landscape in different cell types not yet mapped"]},{"year":2019,"claim":"ChIP-based demonstration that MAFF directly occupies CXCL1 and CSF3 promoters and is required for their activation in myometrial cells provided the first loss-of-function evidence linking MAFF to specific inflammatory gene targets with paracrine signaling consequences.","evidence":"ChIP, siRNA knockdown, RT-qPCR, and paracrine co-culture assay in myometrial/monocytic cells","pmids":["30669188"],"confidence":"Medium","gaps":["Heterodimeric partner at these promoters not identified","In vivo relevance in parturition not tested"]},{"year":2021,"claim":"Multiple studies revealed MAFF-BACH1 heterodimers as context-dependent activators or repressors: activating IL11 under hypoxia in breast cancer (driving STAT3 and metastasis), repressing LDLR under inflammation (reducing cholesterol uptake), and suppressing HBV transcription by competing with HNF-4α — together establishing partner- and promoter-specific functional polarity.","evidence":"ChIP-seq, ChIP-mass spectrometry, RNA-seq, CRISPR knockout, binding-site mutagenesis, in vivo metastasis and atherosclerosis models","pmids":["34262028","33626882","33980595"],"confidence":"High","gaps":["Whether MAFF-BACH1 versus MAFF-BACH2 differ in target gene selectivity not resolved","Structural determinants of activating vs. repressive MAFF-BACH1 complexes unknown"]},{"year":2021,"claim":"circRNA-mediated regulation of MAFF expression—via cia-MAF recruiting TIP60 to the MAFF promoter and circ-ITCH sponging miR-224-5p to stabilize MAFF mRNA—established noncoding RNA layers controlling MAFF abundance with opposing functional outcomes in liver cancer.","evidence":"CRISPR knockout of circRNA, ChIP for TIP60, luciferase reporter assay, RNA pull-down, xenograft models","pmids":["34403373","31969212"],"confidence":"Medium","gaps":["Whether these circRNA mechanisms operate in normal tissues unknown","Relative contribution of transcriptional vs. post-transcriptional MAFF regulation not quantified"]},{"year":2024,"claim":"Discovery that BAP1 deubiquitinates K48-linked ubiquitin on MAFF to stabilize it, with stabilized MAFF upregulating DUSP5 to suppress ERK signaling, revealed a post-translational axis controlling MAFF protein levels and linked MAFF to MAPK pathway regulation in colorectal cancer.","evidence":"Quantitative proteomics, DUB library screen, K48-ubiquitin-specific assays, MAFF overexpression/knockdown, xenograft models","pmids":["39151323"],"confidence":"High","gaps":["E3 ligase responsible for K48-ubiquitination of MAFF not identified","Whether BAP1-MAFF axis operates in normal tissues unclear"]},{"year":2024,"claim":"Genome-wide CRISPR screens and ChIP-seq in lung adenocarcinoma identified MAFF as a direct transcriptional regulator of SLC7A11 (ferroptosis) and CDK6/CDKN2C (cell cycle), with its own expression controlled by the cAMP/PKA/CREB1 pathway, establishing MAFF as a node integrating stress signaling with cell fate decisions.","evidence":"CRISPR screens, ChIP-seq, RNA-seq, single-cell RNA-seq, xenograft models, pharmacological cAMP/PKA pathway analysis","pmids":["38266355"],"confidence":"High","gaps":["Whether MAFF acts as activator or repressor at the SLC7A11 promoter is context-dependent and not fully resolved","Role of specific heterodimeric partners at these promoters not determined"]},{"year":2025,"claim":"Recent studies expanded the MAFF target repertoire to include CLCF1 (with BACH1, activating STAT3 in liver I/R injury), VMP1 (regulated via YTHDC1-mediated mRNA stabilization), CCND1 (activated upon ZNF655-promoted nuclear translocation), KLF5 (repressed by MAFF, derepressed by HDAC6-mediated MAFF deacetylation), AKR1C1 (ferroptosis inhibition), and PTGS2/OXTR (with NRF2 in myometrial contraction), while demonstrating MAFF suppresses YAP1 nuclear translocation to inhibit angiogenesis.","evidence":"CUT&Tag, ChIP, dual-luciferase assays, Co-IP, m6A/mRNA stability assays, HDAC6 inhibition, xenograft and disease mouse models","pmids":["40169936","40054588","41088232","39412062","41206944","41854048","41287850"],"confidence":"Medium","gaps":["Mechanisms of MAFF partner selection across these diverse contexts not unified","HDAC6-mediated deacetylation site on MAFF not mapped","How ZNF655 promotes MAFF nuclear translocation mechanistically undefined"]},{"year":null,"claim":"Key unresolved questions include the structural basis for MAFF's partner selectivity among CNC and Bach proteins, the identity of E3 ubiquitin ligase(s) targeting MAFF for degradation, the specific acetylation and ubiquitination sites on MAFF, and whether compound small Maf knockout reveals essential non-redundant functions in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of MAFF heterodimer","E3 ligase for MAFF K48-ubiquitination unidentified","Compound mafF/mafG/mafK knockout phenotype not fully characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,3,8,9,12,13,16,17,20,22,23,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,7,8,9,12,13,16,17,20,22,23,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7,20]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,7,8,9,12,13,16,17,20,22,23,24]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,15,18,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[17,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[17]}],"complexes":[],"partners":["BACH1","NRF2","NRF1","BAP1","BATF3","ZNF655","YTHDC1"],"other_free_text":[]},"mechanistic_narrative":"MAFF is a small nuclear bZIP transcription factor that lacks an intrinsic transactivation domain and functions as an obligatory heterodimerization 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 heterodimer function—activation or repression—depends on the binding partner and promoter context [PMID:8361754, PMID:12490281, PMID:27058431]. MAFF directly regulates diverse target gene promoters including IL11, LDLR, CLCF1, CXCL1, CSF3, SLC7A11, CDK6, AKR1C1, CCND1, ZNF711, PTGS2, OXTR, and the HBV core promoter, thereby controlling processes spanning inflammation, lipid metabolism, ferroptosis, cell cycle progression, and viral replication [PMID:34262028, PMID:33626882, PMID:38266355, PMID:33980595, PMID:30669188]. MAFF expression is transcriptionally induced by proinflammatory cytokines (IL-1β, TNF) via NF-κB, by HIF under hypoxia, and by the cAMP/PKA/CREB1 pathway, while its protein stability is regulated by BAP1-mediated K48-deubiquitination and HDAC6-mediated deacetylation [PMID:16371591, PMID:33980595, PMID:38266355, PMID:39151323, PMID:39412062]. Despite broad tissue expression, mafF-null mice develop normally, reflecting functional redundancy among small Maf family members [PMID:10409670]."},"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): History, structure and function.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27058431","citation_count":198,"is_preprint":false},{"pmid":"8361754","id":"PMC_8361754","title":"Two new members of the maf oncogene family, mafK and mafF, encode nuclear b-Zip proteins lacking putative trans-activator domain.","date":"1993","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8361754","citation_count":162,"is_preprint":false},{"pmid":"22721719","id":"PMC_22721719","title":"The small MAF transcription factors MAFF, MAFG and MAFK: current knowledge and perspectives.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22721719","citation_count":127,"is_preprint":false},{"pmid":"34262028","id":"PMC_34262028","title":"The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling.","date":"2021","source":"Nature 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1990)","url":"https://pubmed.ncbi.nlm.nih.gov/39151323","citation_count":12,"is_preprint":false},{"pmid":"16549056","id":"PMC_16549056","title":"The novel human gene MIP functions as a co-activator of hMafF.","date":"2006","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/16549056","citation_count":11,"is_preprint":false},{"pmid":"23889108","id":"PMC_23889108","title":"DNA modification in carcinogen risk assessment in relation to diet: recent advances and some perspectives from a MAFF workshop.","date":"1997","source":"Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/23889108","citation_count":9,"is_preprint":false},{"pmid":"24213545","id":"PMC_24213545","title":"Transformation of opium poppy (Papaver somniferum L.) with Agrobacterium rhizogenes MAFF 03-01724.","date":"1992","source":"Plant cell 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signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40054588","citation_count":2,"is_preprint":false},{"pmid":"19723544","id":"PMC_19723544","title":"Establish a recombinant yeast detection system to study the effect of MIP on transactivation function of hMafF in US2-driven gene transcription.","date":"2009","source":"Journal of microbiological methods","url":"https://pubmed.ncbi.nlm.nih.gov/19723544","citation_count":1,"is_preprint":false},{"pmid":"41206944","id":"PMC_41206944","title":"MAFF drives pancreatic cancer progression through AKR1C1-mediated inhibition of ferroptosis.","date":"2025","source":"QJM : monthly journal of the Association of Physicians","url":"https://pubmed.ncbi.nlm.nih.gov/41206944","citation_count":1,"is_preprint":false},{"pmid":"40665213","id":"PMC_40665213","title":"Immunosenescence-Related Gene MAFF is Involved in Immune Regulation and Malignant Progression in Pancreatic Adenocarcinoma.","date":"2025","source":"Biological procedures 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40936936","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21630,"output_tokens":5867,"usd":0.076448},"stage2":{"model":"claude-opus-4-6","input_tokens":9498,"output_tokens":3430,"usd":0.19986},"total_usd":0.276308,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"MafF is a nuclear bZIP protein that lacks a transcriptional activation domain (N-terminal acidic domain), localizes to the nucleus, and does not induce morphological transformation of chicken embryo fibroblasts but can weakly induce colony formation in soft agar when overexpressed via retroviral vector.\",\n      \"method\": \"Structural analysis, retroviral overexpression, immunofluorescence, soft agar colony assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and functional assay in cells, single lab\",\n      \"pmids\": [\"8361754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human MafF (hMafF) binds specifically to the US-2 DNA element in the oxytocin receptor (OTR) gene promoter, as demonstrated by electrophoretic mobility shift assay, and its protein is preferentially expressed in term myometrium, supporting a role in OTR gene upregulation at parturition.\",\n      \"method\": \"Yeast one-hybrid screen, EMSA, Northern/Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct DNA-binding assay with EMSA, single lab\",\n      \"pmids\": [\"10527846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MafF is dispensable for normal development in mice: homozygous mafF null mutant mice are born in normal Mendelian ratios with no obvious functional deficiencies, and lacZ knock-in reveals prominent expression in gut, lung, liver, outflow tract of heart, cartilage, bone membrane, and skin but not in hematopoietic cells.\",\n      \"method\": \"Gene targeting (knockout), lacZ reporter knock-in, developmental expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function mouse model with defined phenotypic readout, replicated tissue expression\",\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 on gamma-globin, beta-globin, or GCS1 promoters in multiple cell lines, whereas MafF/CNC heterodimers act as weak transcriptional activators; in combination with Jun on the GCS1 promoter, MafF shows a specific regulatory role.\",\n      \"method\": \"Co-immunoprecipitation, promoter-reporter assays, overexpression in multiple cell lines\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction and functional reporter assays, multiple promoters tested\",\n      \"pmids\": [\"12490281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"mafF mRNA expression is induced to the greatest extent among the three small Maf genes by electrophile response element (EpRE) activators PDTC and PEITC (but not tBHQ) in HepG2 cells, and this induction is transcriptionally mediated, indicating mafF is a stress-responsive gene regulated via mechanisms distinct from mafG and mafK.\",\n      \"method\": \"Northern/RT-PCR, actinomycin D transcription block, multiple cell lines\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mRNA induction assays in multiple lines, transcriptional mechanism confirmed by actinomycin D\",\n      \"pmids\": [\"11772409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAFF transcript and protein levels are rapidly induced (within 30 min) by proinflammatory cytokines IL-1β and TNF in PHM1-31 myometrial cells at the transcriptional level (blocked by actinomycin D); this induction is specific to MAFF and not shared by MAFG or MAFK.\",\n      \"method\": \"RT-PCR, Western blot with MAFF-specific antiserum, actinomycin D block, time-course experiments\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein-level confirmation, actinomycin D mechanistic validation, specificity shown for MAFF vs paralogs\",\n      \"pmids\": [\"16371591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A novel protein MIP (MafF interacting protein) interacts with hMafF via its coiled-coil domain binding to the leucine zipper of hMafF; this interaction causes MIP to translocate from the cytoplasm to the nucleolus; co-expression of MIP and hMafF (but not either alone) activates transcription from a promoter containing US2 elements.\",\n      \"method\": \"In vitro pull-down, co-immunoprecipitation, subcellular localization by fluorescence microscopy, promoter-reporter assay, domain truncation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo interaction with domain mapping and functional reporter readout\",\n      \"pmids\": [\"16549056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Small Maf proteins including MafF form homodimers (acting as transcriptional repressors lacking activation domain) and heterodimers with CNC proteins (p45 NF-E2, Nrf1, Nrf2, Nrf3) and Bach proteins (Bach1, Bach2); CNC and Bach proteins cannot bind DNA as monomers and require sMaf as obligatory partners; heterodimer function (activation or repression) depends on the partner.\",\n      \"method\": \"Review integrating prior biochemical, genetic, and structural data from multiple labs\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — extensively replicated across labs with biochemical, genetic, and structural validation\",\n      \"pmids\": [\"27058431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAFF directly binds to the CXCL1 and CSF3 gene promoters and is required for their transcriptional activation in myometrial cells; MAFF knockdown significantly reduces CXCL1 and CSF3 transcript and protein levels, and MAFF-dependent signaling in myometrial cells can regulate cytokine and matrix metalloproteinase expression in THP-1 monocytic cells in a paracrine fashion.\",\n      \"method\": \"siRNA knockdown, chromatin immunoprecipitation (ChIP), RT-qPCR, protein measurements, paracrine co-culture assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct binding, loss-of-function confirms transcriptional dependency\",\n      \"pmids\": [\"30669188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAFF forms a heterodimer with BACH1 that directly targets and transcriptionally activates the IL11 gene promoter in hypoxic breast cancer cells; IL11 activation leads to downstream STAT3 signaling to promote tumor invasion and metastasis; MAFF expression is induced by HIF under hypoxia.\",\n      \"method\": \"ChIP-seq, RNA-seq, siRNA knockdown, overexpression, invasion assays, in vivo metastasis models, IL11 inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq + RNA-seq + functional rescue with multiple orthogonal methods including in vivo\",\n      \"pmids\": [\"34262028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAFF transcription is activated by a circRNA (cia-MAF) that binds to the MAFF promoter and recruits the TIP60 histone acetyltransferase complex; loss of cia-MAF reduces TIP60 complex binding at the MAFF promoter and decreases MAFF expression, impacting liver tumor-initiating cell self-renewal and metastasis.\",\n      \"method\": \"circRNA knockout (CRISPR), promoter binding assays, ChIP for TIP60 complex, overexpression, xenograft models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with defined mechanistic readout, ChIP confirms TIP60 recruitment\",\n      \"pmids\": [\"34403373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In hepatocellular carcinoma, MafF is a direct target of miR-224-5p; circular RNA circ-ITCH sponges miR-224-5p to stabilize MafF expression; MafF overexpression inhibits HCC cell proliferation and induces apoptosis, acting as a tumor suppressor.\",\n      \"method\": \"Luciferase reporter assay, RNA pull-down assay, lentiviral overexpression, rescue experiments, proliferation and apoptosis assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct miRNA target validation with luciferase assay plus RNA pull-down and rescue\",\n      \"pmids\": [\"31969212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MafF suppresses transcription from the HBV core promoter by physically binding to the promoter and competitively inhibiting HNF-4α binding to an overlapping sequence in enhancer II (EnhII); MafF expression is induced by IL-1β or TNF-α in an NF-κB-dependent manner.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 knockout, ChIP, overexpression with mutant binding site, HBV reporter virus, NF-κB inhibition\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP direct binding, competitive inhibition shown by binding-site mutation, CRISPR KO, multiple cell models\",\n      \"pmids\": [\"33980595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAFF positively correlates with LDLR expression in non-inflammatory conditions but, upon LPS stimulation, forms heterodimers with BACH1 that bind the MAF recognition element (MARE) in the LDLR promoter to transcriptionally downregulate LDLR expression; BACH1 is identified as MAFF's partner under inflammatory conditions by ChIP-mass spectrometry.\",\n      \"method\": \"ChIP-seq, ChIP-mass spectrometry (ChIP-MS), siRNA knockdown, overexpression, in vivo mouse experiments, human patient correlation\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-MS for partner identification, ChIP-seq for binding site, in vitro and in vivo validation\",\n      \"pmids\": [\"33626882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-320a directly targets MafF mRNA (validated by RIP-Seq and luciferase reporter assay); overexpression of miR-320a inhibits MafF protein expression, increases ROS, inhibits β-cell proliferation, and induces apoptosis, causing pancreatic β-cell dysfunction.\",\n      \"method\": \"RIP-Seq, luciferase reporter assay, Western blotting, 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 — direct target validation by luciferase and RIP-Seq, in vivo AAV model with functional readout\",\n      \"pmids\": [\"34631276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAP1, a nuclear deubiquitinating enzyme, binds to MAFF and removes K48-linked ubiquitin chains, stabilizing MAFF protein; stabilized MAFF upregulates DUSP5 expression, resulting in inhibition of ERK phosphorylation and suppression of colorectal cancer growth.\",\n      \"method\": \"Quantitative proteomics, Co-IP, DUB library screen, ubiquitination assays (K48-specific), MAFF overexpression/knockdown, in vitro and xenograft models, RNA-seq\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical deubiquitination assay, K48-ubiquitin specificity, functional rescue with downstream pathway validation\",\n      \"pmids\": [\"39151323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAFF directly binds to the ZNF711 promoter and represses its transcription; MAFF also interacts with BATF3 (demonstrated by co-immunoprecipitation and co-localization), and BATF3 similarly binds the ZNF711 promoter; simultaneous knockdown of BATF3 and MAFF phenocopies single knockdowns on ZNF711 transcription and apoptosis, indicating MAFF-BATF3 heterodimer represses ZNF711.\",\n      \"method\": \"Dual luciferase assay, ChIP-PCR, Co-IP, immunofluorescence, knockdown rescue experiments\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding confirmed by ChIP, protein interaction by Co-IP, epistasis by double knockdown\",\n      \"pmids\": [\"38908812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAFF regulates ferroptosis and cell cycle progression in lung adenocarcinoma by directly controlling transcription of SLC7A11, CDK6, and CDKN2C (identified by ChIP-seq and RNA-seq); MAFF loss promotes cell cycle G1-to-S progression and reduces ferroptosis sensitivity; the cAMP/PKA/CREB1 intracellular pathway upregulates MAFF expression in response to cisplatin or ionizing radiation.\",\n      \"method\": \"CRISPR screens, ChIP-seq, RNA-seq, single-cell RNA-seq, xenograft models, pharmacological cAMP/PKA pathway analysis\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR loss-of-function, ChIP-seq binding evidence, multiple orthogonal methods in cell and animal models\",\n      \"pmids\": [\"38266355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAFF and BACH1 form a heterodimer that directly binds to the CLCF1 gene promoter (identified by CUT&Tag and RNA-seq) to transcriptionally activate CLCF1, which subsequently activates STAT3 signaling to protect against hepatic ischemia-reperfusion injury by reducing apoptosis and inflammation.\",\n      \"method\": \"CUT&Tag, RNA-seq, adenovirus-mediated overexpression, mouse I/R model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CUT&Tag for direct binding, in vivo model, single lab\",\n      \"pmids\": [\"40169936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDC1 (an m6A reader) promotes nuclear export and stability of MAFF mRNA, enhancing MAFF translation; MAFF in turn transcriptionally activates VMP1, protecting hepatocytes from oxidative stress in ischemia/reperfusion injury.\",\n      \"method\": \"Knockdown/overexpression of YTHDC1 and MAFF, VMP1 rescue experiments, mouse I/R model, mechanistic mRNA stability/export assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue experiments and defined molecular pathway, 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 directly binds the CCND1 promoter and activates its transcription, driving proliferation and stemness; MAFF knockdown phenocopies ZNF655 depletion.\",\n      \"method\": \"Co-IP, ChIP, reporter assay, knockdown/overexpression, xenograft models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct promoter binding, nuclear translocation assay, rescue experiments\",\n      \"pmids\": [\"41088232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAFF suppresses nuclear translocation of YAP1 in non-small cell lung cancer cells, reducing downstream VEGF and CTGF expression and inhibiting angiogenesis; MAFF overexpression reduces tumor growth and microvessel density in vivo.\",\n      \"method\": \"Western blot, immunofluorescence, overexpression, xenograft models, IHC for microvessel density\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization assay (IF for YAP1 nuclear translocation), in vivo xenograft validation\",\n      \"pmids\": [\"41287850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC6 deacetylates MAFF to suppress its expression; loss of MAFF derepresses KLF5 transcription (MAFF directly suppresses KLF5 promoter activity as shown by ChIP and dual luciferase reporter assay), thereby enhancing renal fibrosis and inflammation in lupus nephritis.\",\n      \"method\": \"ChIP, dual luciferase reporter assay, HDAC6 inhibition, overexpression/knockdown, in vitro and MRL/lpr mouse model\",\n      \"journal\": \"Renal failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding by ChIP and luciferase, deacetylation mechanism, in vivo model\",\n      \"pmids\": [\"39412062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRF2 and MAFF directly target the promoters of contraction-associated protein genes PTGS2 and OXTR (confirmed by dual-luciferase reporter assay) downstream of melatonin-MT2 receptor-PKC signaling; silencing NRF2 or MAFF reduces contraction-associated protein expression and attenuates myometrial contractility.\",\n      \"method\": \"Dual-luciferase reporter assay, siRNA knockdown, collagen gel contraction assay, pharmacological receptor and kinase inhibition\",\n      \"journal\": \"Journal of pineal research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter targeting validated by luciferase, epistasis confirmed by siRNA, functional contraction readout\",\n      \"pmids\": [\"41854048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAFF directly binds the AKR1C1 promoter (confirmed by dual-luciferase reporter assay) and transcriptionally activates AKR1C1; the MAFF-AKR1C1 axis inhibits ferroptosis by reducing MDA accumulation and lipid ROS, thereby promoting pancreatic cancer progression.\",\n      \"method\": \"Dual-luciferase reporter assay, MAFF knockdown in cell lines, xenograft models, transcriptome sequencing\",\n      \"journal\": \"QJM : monthly journal of the Association of Physicians\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional target validation by luciferase, in vivo xenograft, defined ferroptosis mechanism\",\n      \"pmids\": [\"41206944\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAFF is a nuclear bZIP transcription factor that lacks an intrinsic transactivation domain and functions as an obligatory heterodimeric partner for CNC (Nrf1, Nrf2, NF-E2) and Bach (Bach1, Bach2) proteins, which cannot bind DNA alone; MAFF homodimers act as transcriptional repressors, while its heterodimers can activate or repress target genes (including IL11, LDLR, CLCF1, CXCL1, CSF3, SLC7A11, CDK6, AKR1C1, CCND1, and viral promoters) in a context- and partner-dependent manner; MAFF protein stability is regulated by BAP1-mediated deubiquitination (K48-ubiquitin) and HDAC6-mediated deacetylation, its mRNA is stabilized and exported by the m6A reader YTHDC1 and sponged by circRNAs, its expression is transcriptionally induced by proinflammatory cytokines (IL-1β, TNF) via NF-κB and by HIF under hypoxia, and its nuclear localization can be promoted by ZNF655, enabling it to regulate downstream pathways including STAT3, ERK, YAP1, and ferroptosis in diverse biological contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAFF is a small nuclear bZIP transcription factor that lacks an intrinsic transactivation domain and functions as an obligatory heterodimerization 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 heterodimer function—activation or repression—depends on the binding partner and promoter context [PMID:8361754, PMID:12490281, PMID:27058431]. MAFF directly regulates diverse target gene promoters including IL11, LDLR, CLCF1, CXCL1, CSF3, SLC7A11, CDK6, AKR1C1, CCND1, ZNF711, PTGS2, OXTR, and the HBV core promoter, thereby controlling processes spanning inflammation, lipid metabolism, ferroptosis, cell cycle progression, and viral replication [PMID:34262028, PMID:33626882, PMID:38266355, PMID:33980595, PMID:30669188]. MAFF expression is transcriptionally induced by proinflammatory cytokines (IL-1β, TNF) via NF-κB, by HIF under hypoxia, and by the cAMP/PKA/CREB1 pathway, while its protein stability is regulated by BAP1-mediated K48-deubiquitination and HDAC6-mediated deacetylation [PMID:16371591, PMID:33980595, PMID:38266355, PMID:39151323, PMID:39412062]. Despite broad tissue expression, mafF-null mice develop normally, reflecting functional redundancy among small Maf family members [PMID:10409670].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of MafF as a nuclear bZIP protein lacking a transactivation domain established its structural distinction from large Maf oncoproteins and predicted that it would function through heterodimerization rather than autonomous transcriptional activation.\",\n      \"evidence\": \"Retroviral overexpression, immunofluorescence localization, and transformation assays in chicken embryo fibroblasts\",\n      \"pmids\": [\"8361754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No heterodimeric partners identified at this stage\", \"Weak soft-agar colony formation not independently replicated\", \"DNA-binding specificity not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that MAFF binds the OTR promoter US-2 element and that mafF-null mice develop normally established MAFF as a sequence-specific DNA-binding factor with functional redundancy among small Maf paralogs.\",\n      \"evidence\": \"EMSA for DNA binding; gene-targeted mafF knockout mice with lacZ knock-in for expression mapping\",\n      \"pmids\": [\"10527846\", \"10409670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compound small Maf knockouts not yet tested\", \"Functional consequence of OTR promoter binding in vivo not demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Biochemical demonstration that MafF forms homodimers (repressive) and heterodimers with CNC proteins (activating) on globin and antioxidant promoters defined its dual role as a molecular switch for transcriptional regulation, and identification of electrophile-responsive MAFF induction established it as a stress-responsive gene.\",\n      \"evidence\": \"Co-immunoprecipitation, promoter-reporter assays on multiple promoters; Northern blot with actinomycin D block in HepG2 cells\",\n      \"pmids\": [\"12490281\", \"11772409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of homodimer repression not tested\", \"Whether MafF and MafG/MafK heterodimers differ in target specificity unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Rapid induction of MAFF (but not MAFG/MAFK) by IL-1β and TNF at the transcriptional level revealed MAFF as a uniquely inflammatory-responsive small Maf member, linking it to NF-κB-driven gene programs.\",\n      \"evidence\": \"RT-PCR and Western blot with actinomycin D block in myometrial cells; paralog specificity confirmed\",\n      \"pmids\": [\"16371591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-κB binding to MAFF promoter not directly shown at this point\", \"Downstream inflammatory targets of MAFF not yet identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Consolidation across multiple labs confirmed that small Mafs including MAFF are obligatory partners for CNC (Nrf1–3, NF-E2) and Bach (Bach1, Bach2) proteins, which cannot bind DNA as monomers, establishing the general paradigm for MAFF-dependent transcriptional control.\",\n      \"evidence\": \"Integrative review of biochemical, genetic, and structural data from multiple independent laboratories\",\n      \"pmids\": [\"27058431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for partner selectivity among small Mafs not resolved\", \"Genome-wide binding landscape in different cell types not yet mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ChIP-based demonstration that MAFF directly occupies CXCL1 and CSF3 promoters and is required for their activation in myometrial cells provided the first loss-of-function evidence linking MAFF to specific inflammatory gene targets with paracrine signaling consequences.\",\n      \"evidence\": \"ChIP, siRNA knockdown, RT-qPCR, and paracrine co-culture assay in myometrial/monocytic cells\",\n      \"pmids\": [\"30669188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterodimeric partner at these promoters not identified\", \"In vivo relevance in parturition not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies revealed MAFF-BACH1 heterodimers as context-dependent activators or repressors: activating IL11 under hypoxia in breast cancer (driving STAT3 and metastasis), repressing LDLR under inflammation (reducing cholesterol uptake), and suppressing HBV transcription by competing with HNF-4α — together establishing partner- and promoter-specific functional polarity.\",\n      \"evidence\": \"ChIP-seq, ChIP-mass spectrometry, RNA-seq, CRISPR knockout, binding-site mutagenesis, in vivo metastasis and atherosclerosis models\",\n      \"pmids\": [\"34262028\", \"33626882\", \"33980595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAFF-BACH1 versus MAFF-BACH2 differ in target gene selectivity not resolved\", \"Structural determinants of activating vs. repressive MAFF-BACH1 complexes unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"circRNA-mediated regulation of MAFF expression—via cia-MAF recruiting TIP60 to the MAFF promoter and circ-ITCH sponging miR-224-5p to stabilize MAFF mRNA—established noncoding RNA layers controlling MAFF abundance with opposing functional outcomes in liver cancer.\",\n      \"evidence\": \"CRISPR knockout of circRNA, ChIP for TIP60, luciferase reporter assay, RNA pull-down, xenograft models\",\n      \"pmids\": [\"34403373\", \"31969212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these circRNA mechanisms operate in normal tissues unknown\", \"Relative contribution of transcriptional vs. post-transcriptional MAFF regulation not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that BAP1 deubiquitinates K48-linked ubiquitin on MAFF to stabilize it, with stabilized MAFF upregulating DUSP5 to suppress ERK signaling, revealed a post-translational axis controlling MAFF protein levels and linked MAFF to MAPK pathway regulation in colorectal cancer.\",\n      \"evidence\": \"Quantitative proteomics, DUB library screen, K48-ubiquitin-specific assays, MAFF overexpression/knockdown, xenograft models\",\n      \"pmids\": [\"39151323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for K48-ubiquitination of MAFF not identified\", \"Whether BAP1-MAFF axis operates in normal tissues unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genome-wide CRISPR screens and ChIP-seq in lung adenocarcinoma identified MAFF as a direct transcriptional regulator of SLC7A11 (ferroptosis) and CDK6/CDKN2C (cell cycle), with its own expression controlled by the cAMP/PKA/CREB1 pathway, establishing MAFF as a node integrating stress signaling with cell fate decisions.\",\n      \"evidence\": \"CRISPR screens, ChIP-seq, RNA-seq, single-cell RNA-seq, xenograft models, pharmacological cAMP/PKA pathway analysis\",\n      \"pmids\": [\"38266355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAFF acts as activator or repressor at the SLC7A11 promoter is context-dependent and not fully resolved\", \"Role of specific heterodimeric partners at these promoters not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent studies expanded the MAFF target repertoire to include CLCF1 (with BACH1, activating STAT3 in liver I/R injury), VMP1 (regulated via YTHDC1-mediated mRNA stabilization), CCND1 (activated upon ZNF655-promoted nuclear translocation), KLF5 (repressed by MAFF, derepressed by HDAC6-mediated MAFF deacetylation), AKR1C1 (ferroptosis inhibition), and PTGS2/OXTR (with NRF2 in myometrial contraction), while demonstrating MAFF suppresses YAP1 nuclear translocation to inhibit angiogenesis.\",\n      \"evidence\": \"CUT&Tag, ChIP, dual-luciferase assays, Co-IP, m6A/mRNA stability assays, HDAC6 inhibition, xenograft and disease mouse models\",\n      \"pmids\": [\"40169936\", \"40054588\", \"41088232\", \"39412062\", \"41206944\", \"41854048\", \"41287850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanisms of MAFF partner selection across these diverse contexts not unified\", \"HDAC6-mediated deacetylation site on MAFF not mapped\", \"How ZNF655 promotes MAFF nuclear translocation mechanistically undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for MAFF's partner selectivity among CNC and Bach proteins, the identity of E3 ubiquitin ligase(s) targeting MAFF for degradation, the specific acetylation and ubiquitination sites on MAFF, and whether compound small Maf knockout reveals essential non-redundant functions in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of MAFF heterodimer\", \"E3 ligase for MAFF K48-ubiquitination unidentified\", \"Compound mafF/mafG/mafK knockout phenotype not fully characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 3, 8, 9, 12, 13, 16, 17, 20, 22, 23, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 7, 8, 9, 12, 13, 16, 17, 20, 22, 23, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 7, 8, 9, 12, 13, 16, 17, 20, 22, 23, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 15, 18, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [17, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BACH1\",\n      \"NRF2\",\n      \"NRF1\",\n      \"BAP1\",\n      \"BATF3\",\n      \"ZNF655\",\n      \"YTHDC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}