{"gene":"FASN","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2019,"finding":"FASN-derived saturated fatty acids supply palmitoylation of MYD88 at cysteine 113 via the palmitoyltransferase ZDHHC6; this palmitoylation is required for IRAK4 binding to the MYD88 intermediate domain and downstream TLR/MYD88 signal activation.","method":"Pharmacological FASN inhibition (C75), ZDHHC6 knockdown, site-directed mutagenesis of MYD88 C113, co-immunoprecipitation of IRAK4–MYD88, in vivo sepsis models","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (inhibitor, KD, mutagenesis, Co-IP, in vivo rescue) in one study with rigorous mechanistic dissection","pmids":["31427815"],"is_preprint":false},{"year":2024,"finding":"FASN inhibition reduces palmitoylation of MHC-I, preventing its lysosomal degradation and thereby increasing MHC-I surface levels and antigen presentation; the palmitoyltransferase DHHC3 directly binds MHC-I and negatively regulates its protein levels.","method":"Genetic FASN KO (CRISPR/Cas9), pharmacological FASN inhibitors (orlistat, TVB-2640), Co-IP of DHHC3–MHC-I, palmitoylation assays, CD8+ T-cell cytotoxicity assays, orthotopic mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic KO plus pharmacological inhibition plus direct binding assay plus functional immune readout, replicated in vivo","pmids":["38486485"],"is_preprint":false},{"year":2024,"finding":"ZDHHC20 palmitoylates FASN at cysteines 1471 and 1881, competing with the E3 ubiquitin ligase complex SNX8-TRIM28-mediated ubiquitination; ZDHHC20-mediated palmitoylation stabilizes FASN protein and promotes hepatocarcinogenesis.","method":"Palmitoylation LC-MS, acyl-biotin exchange assay, Co-IP, ubiquitination assays, protein half-life assays, ZDHHC20 knockout mice with chemical HCC induction","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (ABE, LC-MS, Co-IP, ubiquitination, KO mouse) in one study","pmids":["39696259"],"is_preprint":false},{"year":2024,"finding":"ZDHHC21 palmitoylates FASN at Cys1317, destabilizing FASN protein and reducing fatty acid synthesis; loss of ZDHHC21 in DLBCL increases FASN stability and promotes tumor cell proliferation.","method":"Co-IP of ZDHHC21–FASN, palmitoylation assays, site-directed mutagenesis (C1317), in vitro and in vivo DLBCL proliferation assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding (Co-IP), mutagenesis identifying the palmitoylation site, functional rescue experiments in vitro and in vivo","pmids":["38195819"],"is_preprint":false},{"year":2025,"finding":"FASN interacts with mutant p53 (mutp53) and promotes its palmitoylation, which inhibits mutp53 ubiquitination, stabilizes mutp53 protein, and supports gain-of-function oncogenic activity; pharmacological or genetic FASN inhibition suppresses mutp53 palmitoylation and tumor growth.","method":"Co-IP of FASN–mutp53, palmitoylation assays, FASN genetic inhibition and small-molecule inhibitors, orthotopic/subcutaneous xenograft models, transgenic mice, human tumor organoids","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct interaction demonstrated by Co-IP, palmitoylation mechanistically linked to ubiquitination competition, validated across multiple in vivo models and organoids","pmids":["39971971"],"is_preprint":false},{"year":2023,"finding":"FBXW7β, a cytoplasmic FBXW7 isoform, functions as an E3 ubiquitin ligase for FASN, targeting it for degradation; COP9 signalosome subunit 6 (CSN6) associates with both FBXW7β and FASN, promotes FBXW7β autoubiquitination and degradation, thereby preventing FASN ubiquitination and stabilizing FASN to sustain lipogenesis in colorectal cancer.","method":"Co-IP, ubiquitination assays, FBXW7β mutation analysis, CSN6 overexpression/knockdown, patient-derived xenograft experiments","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, ubiquitination assays, mutant FBXW7β functional studies, in vivo PDX validation","pmids":["37202390"],"is_preprint":false},{"year":2023,"finding":"TRIM21 promotes K48-linked ubiquitination and proteasomal degradation of FASN through direct protein–protein interaction, thereby reducing hepatic lipid accumulation and improving metabolic phenotypes in diabetic mice.","method":"Co-IP, ubiquitination (K48-linkage) assays, TRIM21 overexpression/knockdown in obese diabetic mice, rescue with FASN overexpression","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding, K48-ubiquitination characterized, in vivo rescue experiment confirming specificity","pmids":["37249651"],"is_preprint":false},{"year":2023,"finding":"FABP5 interacts with FASN and activates the ubiquitin-proteasome pathway to decrease FASN protein levels, suppressing lipid accumulation and mTOR signaling to promote autophagy in colorectal cancer cells.","method":"Co-IP of FABP5–FASN, ubiquitination assays, FABP5 overexpression/knockdown, in vitro and in vivo functional assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and ubiquitination shown, multiple cell and animal models, single lab","pmids":["37416772"],"is_preprint":false},{"year":2022,"finding":"Deletion of Fasn specifically in mouse embryonic telencephalon (Emx1Cre) causes severe microcephaly due to altered polarity of apical radial glia progenitors and reduced progenitor proliferation; pharmacological FASN inhibition in human forebrain organoids recapitulates the radial glia polarity defect, establishing FASN-dependent de novo lipogenesis as required for cortical brain development.","method":"Conditional Fasn KO (Emx1Cre), pharmacological inhibition in hESC-derived forebrain organoids, immunofluorescence and proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic KO with defined cellular phenotype, replicated with pharmacological inhibition in human organoids across two species","pmids":["34996870"],"is_preprint":false},{"year":2020,"finding":"Neural stem/progenitor cells (NSPCs) expressing a FASN R1819W (mouse R1812W) variant display FASN-dependent lipid accumulation and ER stress that impairs NSPC proliferation; homozygous mice show reduced adult hippocampal NSPC activity and cognitive defects.","method":"Knock-in mouse model (FASN R1812W), hESC lines with FASN R1819W, 3D forebrain organoids, lipid profiling, ER stress markers, behavioral testing","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — variant knock-in mouse plus hESC organoid validation with mechanistic link (lipid accumulation → ER stress → impaired proliferation)","pmids":["32386572"],"is_preprint":false},{"year":2021,"finding":"FASN inhibition elevates pro-apoptotic BH3-only proteins BIM, PUMA, and NOXA; the resulting redox imbalance (palmitate/NADPH-related) heightens mitochondrial apoptotic priming, shifting cancer cells toward BCL-2 dependence and synergizing with BCL-2/BCL-XL inhibitors (navitoclax, venetoclax) to induce cell death.","method":"Pharmacological FASN inhibitors, BIM/PUMA loss-of-function experiments, BH3 profiling, BCL-2 family protein Western blots, breast cancer xenograft models with oral FASNi","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function epistasis (BIM/PUMA KD rescues death), mechanistic link to redox imbalance, in vivo xenograft confirmation","pmids":["34675185"],"is_preprint":false},{"year":2024,"finding":"FASN-produced malonyl-CoA inhibits STING palmitoylation (at C91) in macrophages; FASN inhibition reduces available malonyl-CoA and palmitate, thereby suppressing STING pathway activation and alleviating sepsis-induced liver injury.","method":"Metabolomics, STING-KO mice, FASN inhibitor screening, palmitoylation assays, C91 mutagenesis of STING","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mutagenesis identifies C91 as palmitoylation site, STING-KO in vivo, mechanistic link via malonyl-CoA, single lab","pmids":["38878833"],"is_preprint":false},{"year":2024,"finding":"FASN depletion prevents adaptive PD-L1 induction by interferon-gamma and reduces constitutive PD-L1 overexpression by abolishing PD-L1 post-translational palmitoylation; FASN-deficient cancer cells show enhanced susceptibility to cytokine-activated T-cell killing and suppressed mitochondrial OXPHOS.","method":"CRISPR/Cas9 FASN KO cell lines, real-time T-cell cytotoxicity assays, PD-L1 palmitoylation assays, electron transport chain complex analysis, mathematical modeling","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined immune phenotype and PD-L1 palmitoylation mechanism, single lab, no in vivo validation described","pmids":["39349429"],"is_preprint":false},{"year":2008,"finding":"FBI-1 (ZBTB7A/Pokemon) synergistically activates FASN gene transcription with SREBP-1 by binding the proximal GC-box and SRE/E-box elements of the FASN promoter; FBI-1 alters the binding pattern of Sp1 and SREBP-1 on these elements to drive enhanced transcriptional activation.","method":"Luciferase promoter reporter assays, DNA-protein binding assays (EMSA/ChIP-type), co-transfection of FBI-1, SREBP-1, and Sp1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct promoter binding demonstrated, synergy quantified with multiple reporter constructs and binding competition experiments","pmids":["18682402"],"is_preprint":false},{"year":2023,"finding":"TAF15 binds directly to the FASN promoter and activates its transcription, promoting hepatic steatosis; TAF15 also interacts with p65 (NF-κB) to activate inflammatory signaling independently of FASN.","method":"CUT&TAG chromatin profiling, dual-luciferase reporter assay, Co-IP of TAF15–p65, AAV-mediated hepatocyte-specific TAF15 KD/OE, NASH mouse models, FASN inhibitor rescue","journal":"Liver international","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct promoter occupancy by CUT&TAG, functional reporter assay, direct protein interaction by Co-IP, in vivo rescue by FASN inhibitor","pmids":["37183512"],"is_preprint":false},{"year":2022,"finding":"USP13 deubiquitinase interacts with FASN and enhances FASN protein stability; the enzymatic activity of USP13 is required for this stabilization and for maintenance of SCLC cancer stem cell properties and de novo fatty acid synthesis.","method":"Co-IP of USP13–FASN, enzyme-inactive USP13 mutant rescue experiments, FASN/USP13 KD in SCLC lines and xenografts","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP binding, active-site mutant distinguishes enzymatic dependence, in vivo xenograft data, single lab","pmids":["35898882"],"is_preprint":false},{"year":2024,"finding":"VCP recruits the deubiquitinase USP2 to remove K48-linked ubiquitin chains from FASN, stabilizing FASN protein; domain 2 of VCP and a specific USP2 sequence are critical for their interaction; the VCP/USP2/FASN axis activates autophagy and promotes osteosarcoma progression.","method":"Co-IP combined with mass spectrometry, K48-ubiquitination assays, molecular docking, protein truncation mapping, LC3 fluorescence confocal, TEM, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS, ubiquitination characterization, domain mapping; in vivo validation; single lab","pmids":["39489738"],"is_preprint":false},{"year":2024,"finding":"GSTM3 stabilizes the deubiquitinase USP14, which in turn inhibits ubiquitination and degradation of FASN; elevated FASN sustains lipid synthesis that suppresses radiation-induced ferroptosis in NPC cells, while GSTM3 also independently interacts with and suppresses GPX4.","method":"Co-IP, mass spectrometry, immunofluorescence co-localization, ferroptosis markers, in vitro and xenograft radiosensitivity assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP/MS for interaction mapping, functional ferroptosis readout, in vivo validation; single lab","pmids":["38228715"],"is_preprint":false},{"year":2023,"finding":"CircRREB1 inhibits acetylation-dependent ubiquitination of FASN (preventing proteasomal degradation) and simultaneously induces RanBP2-mediated SUMOylation of FASN to enhance its protein stability, thereby supporting senescence-associated lipid dysregulation in chondrocytes.","method":"CircRREB1 knockdown/overexpression, ubiquitination assays, acetylation assays, SUMOylation assays, intra-articular injection of adenovirus-CircRreb1 in mice","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple PTM assays (ubiquitination, acetylation, SUMOylation) and in vivo reversal experiment; primarily about a circRNA but directly documents FASN PTM mechanisms","pmids":["37640697"],"is_preprint":false},{"year":2023,"finding":"FASN deficiency induces reductive carboxylation by IDH1 that generates cytosolic citrate; this citrate is exported back to mitochondria via the mitochondrial citrate transport protein (CTP), conferring resistance to detachment-induced oxidative stress in anchorage-independent cancer cells.","method":"Metabolic flux analysis (MFA) with stable isotope tracing, IDH1 and CTP genetic inhibition in FASN-deficient cells, oxidative stress assays in spheroids","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — isotope-based MFA is a direct metabolic flux measurement; IDH1/CTP epistasis experiments validate the pathway; single lab","pmids":["37578864"],"is_preprint":false},{"year":2024,"finding":"FASN interacts with SNARE complex components STX17, SNAP29, and VAMP8, and FASN activity is required for autophagosome-lysosome fusion; FASN inhibition (via AMPK activator MK8722) blocks late-stage autophagy by disrupting this FASN–SNARE interaction.","method":"Co-IP/immunofluorescence of FASN with STX17/SNAP29/VAMP8, plasmid rescue, Western blot for autophagy markers, TEM","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and immunofluorescence demonstrate FASN–SNARE interaction, functional consequence (autophagosome-lysosome fusion block) validated; single lab","pmids":["38164137"],"is_preprint":false},{"year":2015,"finding":"TSH/TSHR signaling suppresses FASN expression in mature adipocytes through PKA activation and ERK1/2 phosphorylation (but not JNK); pharmacological inhibition of PKA or ERK partially abolishes TSH-induced FASN downregulation.","method":"TSH treatment of mature adipocytes, PKA/ERK/JNK inhibitors, CREB phosphorylation assays, mRNA and protein quantification","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway dissection using selective inhibitors in primary adipocytes; single lab with multiple inhibitor controls","pmids":["25655684"],"is_preprint":false},{"year":2023,"finding":"ALC-mediated degradation: FASN knockdown in AML cells reduces FASN protein via autophagic degradation; reduced FASN promotes nuclear translocation of transcription factor EB (TFEB) and activation of CLEAR network genes and lysosomal biogenesis to accelerate granulocytic differentiation.","method":"RNAi-mediated FASN knockdown, EGCG treatment, TFEB nuclear translocation assays, CLEAR network gene expression, ATRA differentiation model in APL cell lines","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with defined molecular cascade (FASN → TFEB nuclear translocation → lysosomal biogenesis), functional differentiation phenotype; single lab","pmids":["33742137"],"is_preprint":false},{"year":2021,"finding":"Dihydroartemisinin (DHA) decreases FASN levels, which increases malonylation of mTOR at K1218 and attenuates mTORC1 activity; reduced mTORC1 further inhibits FASN via decreased p70S6K phosphorylation and reduced SREBP-1 binding to the FASN promoter, forming a feedback loop that suppresses retinal vascular dysfunction.","method":"DHA treatment in diabetic mice and HRMECs, siRNA against FASN, K1218 mTOR mutagenesis, malonylation assays, SREBP-1 ChIP at FASN promoter (positions -64 and -55)","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of mTOR K1218, FASN siRNA rescue, ChIP identifies SREBP-1 binding sites; multiple orthogonal methods in single lab","pmids":["34619345"],"is_preprint":false},{"year":2023,"finding":"FASN de novo lipogenesis is required for alveolar type II (AEC2) cell surfactant phospholipid composition; conditional deletion of Fasn in AEC2 cells (FasniΔAEC2) causes altered surfactant phospholipidome, increased surface tension, higher lung inflammation, and more severe airspace enlargement upon cigarette smoke exposure.","method":"AEC2-specific Fasn conditional KO, BALF lipidomics, surfactant tension assay, lung histology, neutrophil/protein BALF quantification","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic KO with defined lipidomic and functional (surface tension) phenotype; single lab","pmids":["37606038"],"is_preprint":false},{"year":2018,"finding":"PKM2 physically interacts with SREBP-1c; PKM2 downregulation reduces SREBP-1c expression via inactivation of the AKT/mTOR signaling pathway, which in turn suppresses FASN transcription and fatty acid synthesis in bladder cancer cells.","method":"Co-IP of PKM2–SREBP-1c, PKM2 knockdown, AKT/mTOR pathway inhibitors, FASN/SREBP-1c Western blots, anti-proliferation assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishes interaction, pathway confirmed by pharmacological inhibition, single lab","pmids":["30221356"],"is_preprint":false},{"year":2023,"finding":"FABP5 interacts with FASN and promotes its degradation via the ubiquitin-proteasome pathway in pancreatic neuroendocrine neoplasms; reduced FASN from FABP5-mediated degradation suppresses Wnt/β-catenin pathway activation and lipid droplet deposition.","method":"Co-IP of FABP5–FASN, ubiquitination assays, FABP5 KD/OE, orlistat FASN inhibitor rescue, in vitro and in vivo assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and ubiquitination assays, functional pathway rescue; single lab","pmids":["37302809"],"is_preprint":false},{"year":2024,"finding":"DPP3 stabilizes FASN protein (through an unspecified mechanism) to promote fatty acid synthesis and tumor cell proliferation and migration in breast cancer.","method":"DPP3 KO in breast cancer cell lines, GSEA of lipid metabolism pathways, Western blot for FASN, metabolomics of free fatty acids","journal":"Acta biochimica et biophysica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — FASN stabilization inferred from KO + Western blot; no direct binding or ubiquitination assay reported for DPP3–FASN interaction; single lab","pmids":["38655619"],"is_preprint":false},{"year":2024,"finding":"Aryl hydrocarbon receptor (AhR) activation by indole-3-acetic acid (3-IAA, from gut Parabacteroides distasonis) downregulates FASN transcription in bladder cancer cells; reduced FASN decreases the MUFA/PUFA ratio, increasing ferroptosis sensitivity.","method":"AhR activation assays, FASN promoter reporter/ChIP-type analysis inferred, FASN knockdown, lipid profiling (MUFA/PUFA), ferroptosis assays in vitro and in vivo","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — AhR–FASN transcriptional link and lipidomic consequence shown; in vitro and in vivo validation; single lab","pmids":["40557796"],"is_preprint":false},{"year":2025,"finding":"Computational studies confirm TVB-3166 and TVB-3664 bind the FASN ketoacyl reductase (KR) domain as uncompetitive inhibitors towards NADPH; FASN inhibition causes NADPH accumulation that parallels sensitivity of PDAC cells to apoptosis.","method":"Computational docking/kinetics of FASNi binding to KR domain, NADPH accumulation assays, BH3 profiling, in vivo PDX xenograft combination experiments","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 1–3 / Moderate — computational KR-domain binding characterization combined with functional NADPH/apoptosis assays and in vivo PDX models; mechanistic link is largely computational for the binding mode","pmids":["39999714"],"is_preprint":false}],"current_model":"FASN is the sole multifunctional enzyme catalyzing de novo long-chain fatty acid synthesis from acetyl-CoA, malonyl-CoA and NADPH; it is regulated at the transcriptional level by SREBP-1/Sp1/FBI-1 and at the protein level by multiple E3 ligases (FBXW7β, TRIM21) that drive K48-ubiquitination/proteasomal degradation, counteracted by deubiquitinases (USP13, USP2) and by palmitoylation at specific cysteine residues (catalyzed by ZDHHC20 at C1471/C1881 and ZDHHC21 at C1317, and opposed by ZDHHC21 in some contexts); the palmitate it produces also drives palmitoylation of downstream signaling proteins including MYD88 (at C113, enabling IRAK4 recruitment), MHC-I (targeting it for lysosomal degradation via DHHC3), PD-L1, and mutant p53 (stabilizing gain-of-function mutp53), thereby coupling lipid metabolism to innate immune signaling, antigen presentation, immune evasion, and oncogenesis; FASN activity is additionally required for radial glia cell polarity and brain development, surfactant phospholipid homeostasis in alveolar type II cells, and autophagosome-lysosome fusion via interaction with SNARE complexes."},"narrative":{"mechanistic_narrative":"FASN is the multifunctional enzyme that drives de novo fatty acid synthesis, with inhibitors binding its ketoacyl reductase domain as uncompetitive inhibitors toward NADPH [PMID:39999714]; through this lipogenic output it couples cellular metabolism to signaling, immunity, and oncogenesis. Its transcription is activated combinatorially: FBI-1/ZBTB7A synergizes with SREBP-1 and Sp1 at the proximal promoter [PMID:18682402], TAF15 directly occupies and activates the promoter to drive hepatic steatosis [PMID:37183512], and the PKM2-SREBP-1c and AKT/mTOR axes feed into the same promoter program [PMID:34619345, PMID:30221356], while AhR activation downregulates FASN transcription [PMID:40557796]. At the protein level FASN abundance is set by a balance of E3 ligases that drive K48-ubiquitination and degradation — FBXW7β (countered by CSN6) [PMID:37202390] and TRIM21 [PMID:37249651] — opposed by deubiquitinases USP13 [PMID:35898882] and VCP-recruited USP2 [PMID:39489738], and by palmitoylation, with ZDHHC20 palmitoylating FASN at C1471/C1881 to block SNX8-TRIM28 ubiquitination and stabilize it [PMID:39696259], while ZDHHC21 palmitoylates C1317 to destabilize it [PMID:38195819]. The palmitate FASN produces is itself a signaling substrate: it supplies palmitoylation of MYD88 at C113 to enable IRAK4 recruitment and TLR signaling [PMID:31427815], palmitoylates MHC-I to target it for lysosomal degradation via DHHC3 [PMID:38486485], palmitoylates PD-L1 to support immune evasion [PMID:39349429], and palmitoylates mutant p53 to block its ubiquitination and sustain gain-of-function oncogenic activity [PMID:39971971]; FASN-derived malonyl-CoA conversely suppresses STING palmitoylation [PMID:38878833]. Beyond metabolism, FASN-dependent lipogenesis is required for radial glia polarity and cortical brain development [PMID:34996870], alveolar type II cell surfactant phospholipid homeostasis [PMID:37606038], and autophagosome-lysosome fusion through interaction with the SNARE components STX17, SNAP29 and VAMP8 [PMID:38164137]. FASN inhibition elevates BH3-only proteins and shifts cancer cells toward BCL-2-dependent apoptotic priming [PMID:34675185] and rewires metabolism toward IDH1-driven reductive carboxylation [PMID:37578864].","teleology":[{"year":2008,"claim":"Established how FASN transcription is combinatorially controlled, showing that the oncoprotein FBI-1/ZBTB7A cooperates with the master lipogenic factor SREBP-1 rather than acting alone.","evidence":"Promoter luciferase reporters, EMSA/ChIP-type DNA binding, and FBI-1/SREBP-1/Sp1 co-transfection","pmids":["18682402"],"confidence":"High","gaps":["Does not address protein-level regulation of FASN","Tissue context of FBI-1 synergy not defined"]},{"year":2015,"claim":"Showed that extracellular hormonal signaling (TSH/TSHR) feeds into FASN expression via PKA and ERK1/2, linking endocrine input to adipocyte lipogenesis.","evidence":"TSH treatment of mature adipocytes with selective PKA/ERK/JNK inhibitors","pmids":["25655684"],"confidence":"Medium","gaps":["Transcription factor target downstream of ERK/PKA not identified","Single cell-type system"]},{"year":2018,"claim":"Connected glycolytic enzyme PKM2 to FASN regulation through SREBP-1c and AKT/mTOR, illustrating cross-talk between glucose and lipid metabolism programs.","evidence":"Co-IP of PKM2-SREBP-1c, PKM2 knockdown, AKT/mTOR inhibitors in bladder cancer cells","pmids":["30221356"],"confidence":"Medium","gaps":["Whether PKM2-SREBP-1c interaction is direct on the FASN promoter not shown","Single lab"]},{"year":2019,"claim":"Defined FASN's lipid product as a signaling currency by showing FASN-derived saturated fatty acids supply MYD88 palmitoylation required for IRAK4 binding and TLR signaling.","evidence":"FASN inhibition (C75), ZDHHC6 knockdown, MYD88 C113 mutagenesis, IRAK4-MYD88 Co-IP, sepsis models","pmids":["31427815"],"confidence":"High","gaps":["Does not address other palmitoylation substrates","Quantitative flux from FASN to MYD88 palmitate not measured"]},{"year":2020,"claim":"Linked a specific FASN variant to neural pathology, showing a knock-in R1819W/R1812W allele causes lipid accumulation and ER stress that impair neural progenitor proliferation and cognition.","evidence":"FASN R1812W knock-in mice, R1819W hESC forebrain organoids, lipid profiling, ER stress markers, behavior","pmids":["32386572"],"confidence":"High","gaps":["Enzymatic consequence of R1819W on FASN catalysis not resolved","No human disease cohort linkage in this entry"]},{"year":2021,"claim":"Explained why FASN inhibition kills cancer cells by showing it raises BH3-only proteins and apoptotic priming, creating BCL-2 dependence exploitable by venetoclax/navitoclax.","evidence":"FASN inhibitors, BIM/PUMA loss-of-function epistasis, BH3 profiling, breast cancer xenografts","pmids":["34675185"],"confidence":"High","gaps":["Precise redox trigger (palmitate vs NADPH) for BH3 induction not isolated"]},{"year":2021,"claim":"Revealed a feedback loop in which FASN levels control mTOR malonylation at K1218 and mTORC1 activity, which in turn regulates FASN transcription via SREBP-1.","evidence":"DHA treatment, FASN siRNA, mTOR K1218 mutagenesis, malonylation assays, SREBP-1 ChIP at FASN promoter","pmids":["34619345"],"confidence":"Medium","gaps":["Whether malonyl-CoA directly malonylates mTOR or via an enzyme unresolved","Generalizability beyond retinal endothelium unknown"]},{"year":2022,"claim":"Established FASN-dependent lipogenesis as essential for cortical development by demonstrating that brain-specific Fasn loss disrupts radial glia polarity and causes microcephaly.","evidence":"Conditional Fasn KO (Emx1Cre) mice and pharmacological inhibition in human forebrain organoids","pmids":["34996870"],"confidence":"High","gaps":["Lipid species mediating polarity not identified","Molecular link from lipogenesis to apical polarity machinery undefined"]},{"year":2022,"claim":"Identified deubiquitination as a FASN stabilizing mechanism, showing USP13's catalytic activity is required to sustain FASN and cancer stem cell properties.","evidence":"USP13-FASN Co-IP, catalytically inactive USP13 mutant rescue, SCLC xenografts","pmids":["35898882"],"confidence":"Medium","gaps":["Ubiquitin chain linkage removed by USP13 not characterized","Single lab"]},{"year":2023,"claim":"Defined the FBXW7β degradation axis and its CSN6 antagonism, establishing how FASN is degraded and how that degradation is blocked in colorectal cancer.","evidence":"Reciprocal Co-IP, ubiquitination assays, FBXW7β mutants, CSN6 manipulation, PDX models","pmids":["37202390"],"confidence":"High","gaps":["FBXW7β degron on FASN not mapped","Generality across tissues not tested"]},{"year":2023,"claim":"Identified TRIM21 as a K48-ubiquitin ligase for FASN that limits hepatic lipid accumulation, connecting FASN turnover to metabolic disease.","evidence":"Co-IP, K48-ubiquitination assays, TRIM21 manipulation in diabetic mice with FASN rescue","pmids":["37249651"],"confidence":"High","gaps":["FASN residues ubiquitinated by TRIM21 not defined","Crosstalk with FBXW7β pathway not addressed"]},{"year":2023,"claim":"Implicated FABP5 as a negative regulator of FASN via ubiquitin-proteasome degradation, coupling FASN loss to mTOR suppression/autophagy and Wnt/β-catenin signaling across two cancer types.","evidence":"FABP5-FASN Co-IP, ubiquitination assays, FABP5 manipulation, orlistat rescue in CRC and pNEN models","pmids":["37416772","37302809"],"confidence":"Medium","gaps":["Whether FABP5 recruits a specific E3 ligase unknown","Direct binding interface not mapped"]},{"year":2023,"claim":"Showed FASN protein is regulated by competing PTMs beyond ubiquitination, with CircRREB1 blocking acetylation-dependent ubiquitination and inducing RanBP2-mediated SUMOylation to stabilize FASN.","evidence":"CircRREB1 manipulation, ubiquitination/acetylation/SUMOylation assays, intra-articular adenovirus in mice","pmids":["37640697"],"confidence":"Medium","gaps":["FASN SUMO and acetylation sites not pinpointed","Mechanism centers on the circRNA rather than direct FASN biochemistry"]},{"year":2023,"claim":"Revealed a metabolic adaptation to FASN loss, showing FASN-deficient cells use IDH1 reductive carboxylation and mitochondrial citrate transport to resist detachment-induced oxidative stress.","evidence":"Stable-isotope metabolic flux analysis with IDH1/CTP epistasis in spheroids","pmids":["37578864"],"confidence":"High","gaps":["Whether this adaptation drives FASN-inhibitor resistance in vivo not established"]},{"year":2023,"claim":"Identified TAF15 as a direct FASN promoter activator promoting steatosis, while also acting through NF-κB independently of FASN.","evidence":"CUT&TAG, dual-luciferase reporter, TAF15-p65 Co-IP, hepatocyte-specific AAV manipulation, NASH models, FASN inhibitor rescue","pmids":["37183512"],"confidence":"High","gaps":["TAF15 binding motif on FASN promoter not defined","Relationship to SREBP-1 occupancy unclear"]},{"year":2023,"claim":"Connected FASN downregulation to differentiation, showing FASN knockdown drives TFEB nuclear translocation and lysosomal biogenesis to accelerate granulocytic differentiation in leukemia.","evidence":"RNAi FASN knockdown, EGCG treatment, TFEB translocation and CLEAR gene assays in APL cells","pmids":["33742137"],"confidence":"Medium","gaps":["Mechanistic link from FASN to TFEB activation not defined","Single lab"]},{"year":2024,"claim":"Defined opposing palmitoyltransferases that set FASN stability, with ZDHHC20 (C1471/C1881) blocking ubiquitination to stabilize FASN and ZDHHC21 (C1317) destabilizing it.","evidence":"ABE/LC-MS palmitoylation mapping, Co-IP, ubiquitination and half-life assays, site mutagenesis, ZDHHC20 KO mice; ZDHHC21 Co-IP/mutagenesis in DLBCL","pmids":["39696259","38195819"],"confidence":"High","gaps":["How a single enzyme family produces opposite stability outcomes mechanistically unresolved","Context-dependence of ZDHHC choice unclear"]},{"year":2024,"claim":"Showed FASN-supplied palmitate controls antigen presentation, with FASN inhibition reducing MHC-I palmitoylation and DHHC3-mediated lysosomal degradation to boost surface MHC-I and T-cell killing.","evidence":"CRISPR FASN KO, FASN inhibitors, DHHC3-MHC-I Co-IP, palmitoylation assays, CD8 cytotoxicity, orthotopic model","pmids":["38486485"],"confidence":"High","gaps":["Direct flux from FASN palmitate to MHC-I acylation not isotope-traced"]},{"year":2024,"claim":"Extended FASN palmitate signaling to immune checkpoint control, showing FASN depletion abolishes PD-L1 palmitoylation and induction, sensitizing cancer cells to T-cell killing.","evidence":"CRISPR FASN KO, PD-L1 palmitoylation assays, real-time T-cell cytotoxicity, ETC analysis","pmids":["39349429"],"confidence":"Medium","gaps":["No in vivo validation in this study","Palmitoyltransferase for PD-L1 not identified here"]},{"year":2024,"claim":"Showed FASN palmitate stabilizes mutant p53, defining a route by which lipogenesis sustains gain-of-function oncogenic p53.","evidence":"FASN-mutp53 Co-IP, palmitoylation/ubiquitination assays, FASN inhibition across xenografts, transgenic mice, organoids","pmids":["39971971"],"confidence":"High","gaps":["mutp53 palmitoylation site not mapped in this entry","Whether wild-type p53 is similarly affected unaddressed"]},{"year":2024,"claim":"Demonstrated FASN-derived malonyl-CoA negatively regulates innate immunity by inhibiting STING palmitoylation at C91, distinguishing malonyl-CoA from palmitate as a regulatory metabolite.","evidence":"Metabolomics, STING-KO mice, FASN inhibitors, STING C91 mutagenesis","pmids":["38878833"],"confidence":"Medium","gaps":["Mechanism by which malonyl-CoA inhibits a palmitoyltransferase not resolved","Single lab"]},{"year":2024,"claim":"Added VCP/USP2 as a FASN-stabilizing deubiquitination module that promotes autophagy and osteosarcoma progression, with the interaction interfaces mapped.","evidence":"Co-IP/MS, K48-ubiquitination assays, docking, truncation mapping, LC3/TEM autophagy readouts, xenografts","pmids":["39489738"],"confidence":"Medium","gaps":["FASN deubiquitination site not defined","Single lab"]},{"year":2024,"claim":"Linked FASN to ferroptosis and radioresistance via a GSTM3-USP14 axis that stabilizes FASN to sustain lipid synthesis.","evidence":"Co-IP/MS, ferroptosis markers, in vitro and xenograft radiosensitivity assays","pmids":["38228715"],"confidence":"Medium","gaps":["Direct USP14-FASN deubiquitination not biochemically isolated from GSTM3-GPX4 effects","Single lab"]},{"year":2024,"claim":"Connected gut-microbial AhR signaling to FASN transcription, showing AhR activation lowers FASN and shifts the MUFA/PUFA ratio to sensitize cells to ferroptosis.","evidence":"AhR activation, FASN knockdown, lipid profiling, ferroptosis assays in vitro and in vivo","pmids":["40557796"],"confidence":"Medium","gaps":["Direct AhR occupancy of FASN promoter inferred not demonstrated","Single lab"]},{"year":2024,"claim":"Implicated DPP3 in FASN protein stabilization to support breast cancer lipogenesis, though the mechanism of stabilization remains undefined.","evidence":"DPP3 KO, GSEA, FASN Western blot, free fatty acid metabolomics","pmids":["38655619"],"confidence":"Low","gaps":["No direct DPP3-FASN binding or ubiquitination assay reported","Stabilization inferred from KO plus Western blot only","Single lab"]},{"year":2024,"claim":"Identified a non-metabolic structural role for FASN in late autophagy, showing FASN interacts with the SNARE machinery and is required for autophagosome-lysosome fusion.","evidence":"Co-IP/immunofluorescence of FASN with STX17/SNAP29/VAMP8, rescue, autophagy markers, TEM","pmids":["38164137"],"confidence":"Medium","gaps":["Whether FASN catalysis or scaffolding mediates fusion not separated","Direct binding interface not mapped"]},{"year":2024,"claim":"Defined FASN's surfactant role, showing AEC2-specific Fasn deletion alters surfactant phospholipid composition and raises surface tension, worsening smoke-induced lung injury.","evidence":"AEC2-specific Fasn KO, BALF lipidomics, surface tension assay, lung histology","pmids":["37606038"],"confidence":"Medium","gaps":["Specific FASN-derived phospholipid precursor not identified","Single lab"]},{"year":2025,"claim":"Resolved the binding mode of clinical FASN inhibitors, showing TVB-3166/TVB-3664 act as uncompetitive inhibitors at the ketoacyl reductase domain toward NADPH, with NADPH accumulation tracking apoptotic sensitivity.","evidence":"Computational docking/kinetics, NADPH accumulation assays, BH3 profiling, PDX combination experiments","pmids":["39999714"],"confidence":"Medium","gaps":["Binding mode is largely computational","Crystallographic confirmation absent"]},{"year":null,"claim":"How the many FASN regulatory inputs — opposing palmitoyltransferases, multiple E3 ligases/DUBs, and transcriptional activators — are integrated in a given cell, and whether FASN's palmitate-donor, malonyl-CoA, and SNARE-scaffolding roles are catalytically separable, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of FASN protein-level regulation","Flux tracing from FASN to specific substrate palmitoylation events lacking","Scaffold vs catalytic contributions of FASN to autophagy not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[29]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[29]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19,20]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,24,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,11,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental 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this palmitoylation is required for IRAK4 binding to the MYD88 intermediate domain and downstream TLR/MYD88 signal activation.\",\n      \"method\": \"Pharmacological FASN inhibition (C75), ZDHHC6 knockdown, site-directed mutagenesis of MYD88 C113, co-immunoprecipitation of IRAK4–MYD88, in vivo sepsis models\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (inhibitor, KD, mutagenesis, Co-IP, in vivo rescue) in one study with rigorous mechanistic dissection\",\n      \"pmids\": [\"31427815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FASN inhibition reduces palmitoylation of MHC-I, preventing its lysosomal degradation and thereby increasing MHC-I surface levels and antigen presentation; the palmitoyltransferase DHHC3 directly binds MHC-I and negatively regulates its protein levels.\",\n      \"method\": \"Genetic FASN KO (CRISPR/Cas9), pharmacological FASN inhibitors (orlistat, TVB-2640), Co-IP of DHHC3–MHC-I, palmitoylation assays, CD8+ T-cell cytotoxicity assays, orthotopic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic KO plus pharmacological inhibition plus direct binding assay plus functional immune readout, replicated in vivo\",\n      \"pmids\": [\"38486485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC20 palmitoylates FASN at cysteines 1471 and 1881, competing with the E3 ubiquitin ligase complex SNX8-TRIM28-mediated ubiquitination; ZDHHC20-mediated palmitoylation stabilizes FASN protein and promotes hepatocarcinogenesis.\",\n      \"method\": \"Palmitoylation LC-MS, acyl-biotin exchange assay, Co-IP, ubiquitination assays, protein half-life assays, ZDHHC20 knockout mice with chemical HCC induction\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (ABE, LC-MS, Co-IP, ubiquitination, KO mouse) in one study\",\n      \"pmids\": [\"39696259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC21 palmitoylates FASN at Cys1317, destabilizing FASN protein and reducing fatty acid synthesis; loss of ZDHHC21 in DLBCL increases FASN stability and promotes tumor cell proliferation.\",\n      \"method\": \"Co-IP of ZDHHC21–FASN, palmitoylation assays, site-directed mutagenesis (C1317), in vitro and in vivo DLBCL proliferation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding (Co-IP), mutagenesis identifying the palmitoylation site, functional rescue experiments in vitro and in vivo\",\n      \"pmids\": [\"38195819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FASN interacts with mutant p53 (mutp53) and promotes its palmitoylation, which inhibits mutp53 ubiquitination, stabilizes mutp53 protein, and supports gain-of-function oncogenic activity; pharmacological or genetic FASN inhibition suppresses mutp53 palmitoylation and tumor growth.\",\n      \"method\": \"Co-IP of FASN–mutp53, palmitoylation assays, FASN genetic inhibition and small-molecule inhibitors, orthotopic/subcutaneous xenograft models, transgenic mice, human tumor organoids\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct interaction demonstrated by Co-IP, palmitoylation mechanistically linked to ubiquitination competition, validated across multiple in vivo models and organoids\",\n      \"pmids\": [\"39971971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXW7β, a cytoplasmic FBXW7 isoform, functions as an E3 ubiquitin ligase for FASN, targeting it for degradation; COP9 signalosome subunit 6 (CSN6) associates with both FBXW7β and FASN, promotes FBXW7β autoubiquitination and degradation, thereby preventing FASN ubiquitination and stabilizing FASN to sustain lipogenesis in colorectal cancer.\",\n      \"method\": \"Co-IP, ubiquitination assays, FBXW7β mutation analysis, CSN6 overexpression/knockdown, patient-derived xenograft experiments\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, ubiquitination assays, mutant FBXW7β functional studies, in vivo PDX validation\",\n      \"pmids\": [\"37202390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM21 promotes K48-linked ubiquitination and proteasomal degradation of FASN through direct protein–protein interaction, thereby reducing hepatic lipid accumulation and improving metabolic phenotypes in diabetic mice.\",\n      \"method\": \"Co-IP, ubiquitination (K48-linkage) assays, TRIM21 overexpression/knockdown in obese diabetic mice, rescue with FASN overexpression\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding, K48-ubiquitination characterized, in vivo rescue experiment confirming specificity\",\n      \"pmids\": [\"37249651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FABP5 interacts with FASN and activates the ubiquitin-proteasome pathway to decrease FASN protein levels, suppressing lipid accumulation and mTOR signaling to promote autophagy in colorectal cancer cells.\",\n      \"method\": \"Co-IP of FABP5–FASN, ubiquitination assays, FABP5 overexpression/knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and ubiquitination shown, multiple cell and animal models, single lab\",\n      \"pmids\": [\"37416772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of Fasn specifically in mouse embryonic telencephalon (Emx1Cre) causes severe microcephaly due to altered polarity of apical radial glia progenitors and reduced progenitor proliferation; pharmacological FASN inhibition in human forebrain organoids recapitulates the radial glia polarity defect, establishing FASN-dependent de novo lipogenesis as required for cortical brain development.\",\n      \"method\": \"Conditional Fasn KO (Emx1Cre), pharmacological inhibition in hESC-derived forebrain organoids, immunofluorescence and proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic KO with defined cellular phenotype, replicated with pharmacological inhibition in human organoids across two species\",\n      \"pmids\": [\"34996870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neural stem/progenitor cells (NSPCs) expressing a FASN R1819W (mouse R1812W) variant display FASN-dependent lipid accumulation and ER stress that impairs NSPC proliferation; homozygous mice show reduced adult hippocampal NSPC activity and cognitive defects.\",\n      \"method\": \"Knock-in mouse model (FASN R1812W), hESC lines with FASN R1819W, 3D forebrain organoids, lipid profiling, ER stress markers, behavioral testing\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — variant knock-in mouse plus hESC organoid validation with mechanistic link (lipid accumulation → ER stress → impaired proliferation)\",\n      \"pmids\": [\"32386572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FASN inhibition elevates pro-apoptotic BH3-only proteins BIM, PUMA, and NOXA; the resulting redox imbalance (palmitate/NADPH-related) heightens mitochondrial apoptotic priming, shifting cancer cells toward BCL-2 dependence and synergizing with BCL-2/BCL-XL inhibitors (navitoclax, venetoclax) to induce cell death.\",\n      \"method\": \"Pharmacological FASN inhibitors, BIM/PUMA loss-of-function experiments, BH3 profiling, BCL-2 family protein Western blots, breast cancer xenograft models with oral FASNi\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function epistasis (BIM/PUMA KD rescues death), mechanistic link to redox imbalance, in vivo xenograft confirmation\",\n      \"pmids\": [\"34675185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FASN-produced malonyl-CoA inhibits STING palmitoylation (at C91) in macrophages; FASN inhibition reduces available malonyl-CoA and palmitate, thereby suppressing STING pathway activation and alleviating sepsis-induced liver injury.\",\n      \"method\": \"Metabolomics, STING-KO mice, FASN inhibitor screening, palmitoylation assays, C91 mutagenesis of STING\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mutagenesis identifies C91 as palmitoylation site, STING-KO in vivo, mechanistic link via malonyl-CoA, single lab\",\n      \"pmids\": [\"38878833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FASN depletion prevents adaptive PD-L1 induction by interferon-gamma and reduces constitutive PD-L1 overexpression by abolishing PD-L1 post-translational palmitoylation; FASN-deficient cancer cells show enhanced susceptibility to cytokine-activated T-cell killing and suppressed mitochondrial OXPHOS.\",\n      \"method\": \"CRISPR/Cas9 FASN KO cell lines, real-time T-cell cytotoxicity assays, PD-L1 palmitoylation assays, electron transport chain complex analysis, mathematical modeling\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined immune phenotype and PD-L1 palmitoylation mechanism, single lab, no in vivo validation described\",\n      \"pmids\": [\"39349429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FBI-1 (ZBTB7A/Pokemon) synergistically activates FASN gene transcription with SREBP-1 by binding the proximal GC-box and SRE/E-box elements of the FASN promoter; FBI-1 alters the binding pattern of Sp1 and SREBP-1 on these elements to drive enhanced transcriptional activation.\",\n      \"method\": \"Luciferase promoter reporter assays, DNA-protein binding assays (EMSA/ChIP-type), co-transfection of FBI-1, SREBP-1, and Sp1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct promoter binding demonstrated, synergy quantified with multiple reporter constructs and binding competition experiments\",\n      \"pmids\": [\"18682402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TAF15 binds directly to the FASN promoter and activates its transcription, promoting hepatic steatosis; TAF15 also interacts with p65 (NF-κB) to activate inflammatory signaling independently of FASN.\",\n      \"method\": \"CUT&TAG chromatin profiling, dual-luciferase reporter assay, Co-IP of TAF15–p65, AAV-mediated hepatocyte-specific TAF15 KD/OE, NASH mouse models, FASN inhibitor rescue\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct promoter occupancy by CUT&TAG, functional reporter assay, direct protein interaction by Co-IP, in vivo rescue by FASN inhibitor\",\n      \"pmids\": [\"37183512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP13 deubiquitinase interacts with FASN and enhances FASN protein stability; the enzymatic activity of USP13 is required for this stabilization and for maintenance of SCLC cancer stem cell properties and de novo fatty acid synthesis.\",\n      \"method\": \"Co-IP of USP13–FASN, enzyme-inactive USP13 mutant rescue experiments, FASN/USP13 KD in SCLC lines and xenografts\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP binding, active-site mutant distinguishes enzymatic dependence, in vivo xenograft data, single lab\",\n      \"pmids\": [\"35898882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VCP recruits the deubiquitinase USP2 to remove K48-linked ubiquitin chains from FASN, stabilizing FASN protein; domain 2 of VCP and a specific USP2 sequence are critical for their interaction; the VCP/USP2/FASN axis activates autophagy and promotes osteosarcoma progression.\",\n      \"method\": \"Co-IP combined with mass spectrometry, K48-ubiquitination assays, molecular docking, protein truncation mapping, LC3 fluorescence confocal, TEM, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS, ubiquitination characterization, domain mapping; in vivo validation; single lab\",\n      \"pmids\": [\"39489738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GSTM3 stabilizes the deubiquitinase USP14, which in turn inhibits ubiquitination and degradation of FASN; elevated FASN sustains lipid synthesis that suppresses radiation-induced ferroptosis in NPC cells, while GSTM3 also independently interacts with and suppresses GPX4.\",\n      \"method\": \"Co-IP, mass spectrometry, immunofluorescence co-localization, ferroptosis markers, in vitro and xenograft radiosensitivity assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP/MS for interaction mapping, functional ferroptosis readout, in vivo validation; single lab\",\n      \"pmids\": [\"38228715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CircRREB1 inhibits acetylation-dependent ubiquitination of FASN (preventing proteasomal degradation) and simultaneously induces RanBP2-mediated SUMOylation of FASN to enhance its protein stability, thereby supporting senescence-associated lipid dysregulation in chondrocytes.\",\n      \"method\": \"CircRREB1 knockdown/overexpression, ubiquitination assays, acetylation assays, SUMOylation assays, intra-articular injection of adenovirus-CircRreb1 in mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple PTM assays (ubiquitination, acetylation, SUMOylation) and in vivo reversal experiment; primarily about a circRNA but directly documents FASN PTM mechanisms\",\n      \"pmids\": [\"37640697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FASN deficiency induces reductive carboxylation by IDH1 that generates cytosolic citrate; this citrate is exported back to mitochondria via the mitochondrial citrate transport protein (CTP), conferring resistance to detachment-induced oxidative stress in anchorage-independent cancer cells.\",\n      \"method\": \"Metabolic flux analysis (MFA) with stable isotope tracing, IDH1 and CTP genetic inhibition in FASN-deficient cells, oxidative stress assays in spheroids\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — isotope-based MFA is a direct metabolic flux measurement; IDH1/CTP epistasis experiments validate the pathway; single lab\",\n      \"pmids\": [\"37578864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FASN interacts with SNARE complex components STX17, SNAP29, and VAMP8, and FASN activity is required for autophagosome-lysosome fusion; FASN inhibition (via AMPK activator MK8722) blocks late-stage autophagy by disrupting this FASN–SNARE interaction.\",\n      \"method\": \"Co-IP/immunofluorescence of FASN with STX17/SNAP29/VAMP8, plasmid rescue, Western blot for autophagy markers, TEM\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and immunofluorescence demonstrate FASN–SNARE interaction, functional consequence (autophagosome-lysosome fusion block) validated; single lab\",\n      \"pmids\": [\"38164137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSH/TSHR signaling suppresses FASN expression in mature adipocytes through PKA activation and ERK1/2 phosphorylation (but not JNK); pharmacological inhibition of PKA or ERK partially abolishes TSH-induced FASN downregulation.\",\n      \"method\": \"TSH treatment of mature adipocytes, PKA/ERK/JNK inhibitors, CREB phosphorylation assays, mRNA and protein quantification\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway dissection using selective inhibitors in primary adipocytes; single lab with multiple inhibitor controls\",\n      \"pmids\": [\"25655684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALC-mediated degradation: FASN knockdown in AML cells reduces FASN protein via autophagic degradation; reduced FASN promotes nuclear translocation of transcription factor EB (TFEB) and activation of CLEAR network genes and lysosomal biogenesis to accelerate granulocytic differentiation.\",\n      \"method\": \"RNAi-mediated FASN knockdown, EGCG treatment, TFEB nuclear translocation assays, CLEAR network gene expression, ATRA differentiation model in APL cell lines\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with defined molecular cascade (FASN → TFEB nuclear translocation → lysosomal biogenesis), functional differentiation phenotype; single lab\",\n      \"pmids\": [\"33742137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dihydroartemisinin (DHA) decreases FASN levels, which increases malonylation of mTOR at K1218 and attenuates mTORC1 activity; reduced mTORC1 further inhibits FASN via decreased p70S6K phosphorylation and reduced SREBP-1 binding to the FASN promoter, forming a feedback loop that suppresses retinal vascular dysfunction.\",\n      \"method\": \"DHA treatment in diabetic mice and HRMECs, siRNA against FASN, K1218 mTOR mutagenesis, malonylation assays, SREBP-1 ChIP at FASN promoter (positions -64 and -55)\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of mTOR K1218, FASN siRNA rescue, ChIP identifies SREBP-1 binding sites; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"34619345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FASN de novo lipogenesis is required for alveolar type II (AEC2) cell surfactant phospholipid composition; conditional deletion of Fasn in AEC2 cells (FasniΔAEC2) causes altered surfactant phospholipidome, increased surface tension, higher lung inflammation, and more severe airspace enlargement upon cigarette smoke exposure.\",\n      \"method\": \"AEC2-specific Fasn conditional KO, BALF lipidomics, surfactant tension assay, lung histology, neutrophil/protein BALF quantification\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic KO with defined lipidomic and functional (surface tension) phenotype; single lab\",\n      \"pmids\": [\"37606038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PKM2 physically interacts with SREBP-1c; PKM2 downregulation reduces SREBP-1c expression via inactivation of the AKT/mTOR signaling pathway, which in turn suppresses FASN transcription and fatty acid synthesis in bladder cancer cells.\",\n      \"method\": \"Co-IP of PKM2–SREBP-1c, PKM2 knockdown, AKT/mTOR pathway inhibitors, FASN/SREBP-1c Western blots, anti-proliferation assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishes interaction, pathway confirmed by pharmacological inhibition, single lab\",\n      \"pmids\": [\"30221356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FABP5 interacts with FASN and promotes its degradation via the ubiquitin-proteasome pathway in pancreatic neuroendocrine neoplasms; reduced FASN from FABP5-mediated degradation suppresses Wnt/β-catenin pathway activation and lipid droplet deposition.\",\n      \"method\": \"Co-IP of FABP5–FASN, ubiquitination assays, FABP5 KD/OE, orlistat FASN inhibitor rescue, in vitro and in vivo assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and ubiquitination assays, functional pathway rescue; single lab\",\n      \"pmids\": [\"37302809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DPP3 stabilizes FASN protein (through an unspecified mechanism) to promote fatty acid synthesis and tumor cell proliferation and migration in breast cancer.\",\n      \"method\": \"DPP3 KO in breast cancer cell lines, GSEA of lipid metabolism pathways, Western blot for FASN, metabolomics of free fatty acids\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — FASN stabilization inferred from KO + Western blot; no direct binding or ubiquitination assay reported for DPP3–FASN interaction; single lab\",\n      \"pmids\": [\"38655619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Aryl hydrocarbon receptor (AhR) activation by indole-3-acetic acid (3-IAA, from gut Parabacteroides distasonis) downregulates FASN transcription in bladder cancer cells; reduced FASN decreases the MUFA/PUFA ratio, increasing ferroptosis sensitivity.\",\n      \"method\": \"AhR activation assays, FASN promoter reporter/ChIP-type analysis inferred, FASN knockdown, lipid profiling (MUFA/PUFA), ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — AhR–FASN transcriptional link and lipidomic consequence shown; in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"40557796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Computational studies confirm TVB-3166 and TVB-3664 bind the FASN ketoacyl reductase (KR) domain as uncompetitive inhibitors towards NADPH; FASN inhibition causes NADPH accumulation that parallels sensitivity of PDAC cells to apoptosis.\",\n      \"method\": \"Computational docking/kinetics of FASNi binding to KR domain, NADPH accumulation assays, BH3 profiling, in vivo PDX xenograft combination experiments\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–3 / Moderate — computational KR-domain binding characterization combined with functional NADPH/apoptosis assays and in vivo PDX models; mechanistic link is largely computational for the binding mode\",\n      \"pmids\": [\"39999714\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FASN is the sole multifunctional enzyme catalyzing de novo long-chain fatty acid synthesis from acetyl-CoA, malonyl-CoA and NADPH; it is regulated at the transcriptional level by SREBP-1/Sp1/FBI-1 and at the protein level by multiple E3 ligases (FBXW7β, TRIM21) that drive K48-ubiquitination/proteasomal degradation, counteracted by deubiquitinases (USP13, USP2) and by palmitoylation at specific cysteine residues (catalyzed by ZDHHC20 at C1471/C1881 and ZDHHC21 at C1317, and opposed by ZDHHC21 in some contexts); the palmitate it produces also drives palmitoylation of downstream signaling proteins including MYD88 (at C113, enabling IRAK4 recruitment), MHC-I (targeting it for lysosomal degradation via DHHC3), PD-L1, and mutant p53 (stabilizing gain-of-function mutp53), thereby coupling lipid metabolism to innate immune signaling, antigen presentation, immune evasion, and oncogenesis; FASN activity is additionally required for radial glia cell polarity and brain development, surfactant phospholipid homeostasis in alveolar type II cells, and autophagosome-lysosome fusion via interaction with SNARE complexes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FASN is the multifunctional enzyme that drives de novo fatty acid synthesis, with inhibitors binding its ketoacyl reductase domain as uncompetitive inhibitors toward NADPH [#29]; through this lipogenic output it couples cellular metabolism to signaling, immunity, and oncogenesis. Its transcription is activated combinatorially: FBI-1/ZBTB7A synergizes with SREBP-1 and Sp1 at the proximal promoter [#13], TAF15 directly occupies and activates the promoter to drive hepatic steatosis [#14], and the PKM2-SREBP-1c and AKT/mTOR axes feed into the same promoter program [#23, #25], while AhR activation downregulates FASN transcription [#28]. At the protein level FASN abundance is set by a balance of E3 ligases that drive K48-ubiquitination and degradation — FBXW7\\u03b2 (countered by CSN6) [#5] and TRIM21 [#6] — opposed by deubiquitinases USP13 [#15] and VCP-recruited USP2 [#16], and by palmitoylation, with ZDHHC20 palmitoylating FASN at C1471/C1881 to block SNX8-TRIM28 ubiquitination and stabilize it [#2], while ZDHHC21 palmitoylates C1317 to destabilize it [#3]. The palmitate FASN produces is itself a signaling substrate: it supplies palmitoylation of MYD88 at C113 to enable IRAK4 recruitment and TLR signaling [#0], palmitoylates MHC-I to target it for lysosomal degradation via DHHC3 [#1], palmitoylates PD-L1 to support immune evasion [#12], and palmitoylates mutant p53 to block its ubiquitination and sustain gain-of-function oncogenic activity [#4]; FASN-derived malonyl-CoA conversely suppresses STING palmitoylation [#11]. Beyond metabolism, FASN-dependent lipogenesis is required for radial glia polarity and cortical brain development [#8], alveolar type II cell surfactant phospholipid homeostasis [#24], and autophagosome-lysosome fusion through interaction with the SNARE components STX17, SNAP29 and VAMP8 [#20]. FASN inhibition elevates BH3-only proteins and shifts cancer cells toward BCL-2-dependent apoptotic priming [#10] and rewires metabolism toward IDH1-driven reductive carboxylation [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established how FASN transcription is combinatorially controlled, showing that the oncoprotein FBI-1/ZBTB7A cooperates with the master lipogenic factor SREBP-1 rather than acting alone.\",\n      \"evidence\": \"Promoter luciferase reporters, EMSA/ChIP-type DNA binding, and FBI-1/SREBP-1/Sp1 co-transfection\",\n      \"pmids\": [\"18682402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address protein-level regulation of FASN\", \"Tissue context of FBI-1 synergy not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that extracellular hormonal signaling (TSH/TSHR) feeds into FASN expression via PKA and ERK1/2, linking endocrine input to adipocyte lipogenesis.\",\n      \"evidence\": \"TSH treatment of mature adipocytes with selective PKA/ERK/JNK inhibitors\",\n      \"pmids\": [\"25655684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor target downstream of ERK/PKA not identified\", \"Single cell-type system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected glycolytic enzyme PKM2 to FASN regulation through SREBP-1c and AKT/mTOR, illustrating cross-talk between glucose and lipid metabolism programs.\",\n      \"evidence\": \"Co-IP of PKM2-SREBP-1c, PKM2 knockdown, AKT/mTOR inhibitors in bladder cancer cells\",\n      \"pmids\": [\"30221356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PKM2-SREBP-1c interaction is direct on the FASN promoter not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined FASN's lipid product as a signaling currency by showing FASN-derived saturated fatty acids supply MYD88 palmitoylation required for IRAK4 binding and TLR signaling.\",\n      \"evidence\": \"FASN inhibition (C75), ZDHHC6 knockdown, MYD88 C113 mutagenesis, IRAK4-MYD88 Co-IP, sepsis models\",\n      \"pmids\": [\"31427815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address other palmitoylation substrates\", \"Quantitative flux from FASN to MYD88 palmitate not measured\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked a specific FASN variant to neural pathology, showing a knock-in R1819W/R1812W allele causes lipid accumulation and ER stress that impair neural progenitor proliferation and cognition.\",\n      \"evidence\": \"FASN R1812W knock-in mice, R1819W hESC forebrain organoids, lipid profiling, ER stress markers, behavior\",\n      \"pmids\": [\"32386572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic consequence of R1819W on FASN catalysis not resolved\", \"No human disease cohort linkage in this entry\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Explained why FASN inhibition kills cancer cells by showing it raises BH3-only proteins and apoptotic priming, creating BCL-2 dependence exploitable by venetoclax/navitoclax.\",\n      \"evidence\": \"FASN inhibitors, BIM/PUMA loss-of-function epistasis, BH3 profiling, breast cancer xenografts\",\n      \"pmids\": [\"34675185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise redox trigger (palmitate vs NADPH) for BH3 induction not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a feedback loop in which FASN levels control mTOR malonylation at K1218 and mTORC1 activity, which in turn regulates FASN transcription via SREBP-1.\",\n      \"evidence\": \"DHA treatment, FASN siRNA, mTOR K1218 mutagenesis, malonylation assays, SREBP-1 ChIP at FASN promoter\",\n      \"pmids\": [\"34619345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether malonyl-CoA directly malonylates mTOR or via an enzyme unresolved\", \"Generalizability beyond retinal endothelium unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established FASN-dependent lipogenesis as essential for cortical development by demonstrating that brain-specific Fasn loss disrupts radial glia polarity and causes microcephaly.\",\n      \"evidence\": \"Conditional Fasn KO (Emx1Cre) mice and pharmacological inhibition in human forebrain organoids\",\n      \"pmids\": [\"34996870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid species mediating polarity not identified\", \"Molecular link from lipogenesis to apical polarity machinery undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified deubiquitination as a FASN stabilizing mechanism, showing USP13's catalytic activity is required to sustain FASN and cancer stem cell properties.\",\n      \"evidence\": \"USP13-FASN Co-IP, catalytically inactive USP13 mutant rescue, SCLC xenografts\",\n      \"pmids\": [\"35898882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage removed by USP13 not characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the FBXW7\\u03b2 degradation axis and its CSN6 antagonism, establishing how FASN is degraded and how that degradation is blocked in colorectal cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, FBXW7\\u03b2 mutants, CSN6 manipulation, PDX models\",\n      \"pmids\": [\"37202390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FBXW7\\u03b2 degron on FASN not mapped\", \"Generality across tissues not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified TRIM21 as a K48-ubiquitin ligase for FASN that limits hepatic lipid accumulation, connecting FASN turnover to metabolic disease.\",\n      \"evidence\": \"Co-IP, K48-ubiquitination assays, TRIM21 manipulation in diabetic mice with FASN rescue\",\n      \"pmids\": [\"37249651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FASN residues ubiquitinated by TRIM21 not defined\", \"Crosstalk with FBXW7\\u03b2 pathway not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated FABP5 as a negative regulator of FASN via ubiquitin-proteasome degradation, coupling FASN loss to mTOR suppression/autophagy and Wnt/\\u03b2-catenin signaling across two cancer types.\",\n      \"evidence\": \"FABP5-FASN Co-IP, ubiquitination assays, FABP5 manipulation, orlistat rescue in CRC and pNEN models\",\n      \"pmids\": [\"37416772\", \"37302809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FABP5 recruits a specific E3 ligase unknown\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed FASN protein is regulated by competing PTMs beyond ubiquitination, with CircRREB1 blocking acetylation-dependent ubiquitination and inducing RanBP2-mediated SUMOylation to stabilize FASN.\",\n      \"evidence\": \"CircRREB1 manipulation, ubiquitination/acetylation/SUMOylation assays, intra-articular adenovirus in mice\",\n      \"pmids\": [\"37640697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FASN SUMO and acetylation sites not pinpointed\", \"Mechanism centers on the circRNA rather than direct FASN biochemistry\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a metabolic adaptation to FASN loss, showing FASN-deficient cells use IDH1 reductive carboxylation and mitochondrial citrate transport to resist detachment-induced oxidative stress.\",\n      \"evidence\": \"Stable-isotope metabolic flux analysis with IDH1/CTP epistasis in spheroids\",\n      \"pmids\": [\"37578864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this adaptation drives FASN-inhibitor resistance in vivo not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified TAF15 as a direct FASN promoter activator promoting steatosis, while also acting through NF-\\u03baB independently of FASN.\",\n      \"evidence\": \"CUT&TAG, dual-luciferase reporter, TAF15-p65 Co-IP, hepatocyte-specific AAV manipulation, NASH models, FASN inhibitor rescue\",\n      \"pmids\": [\"37183512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TAF15 binding motif on FASN promoter not defined\", \"Relationship to SREBP-1 occupancy unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected FASN downregulation to differentiation, showing FASN knockdown drives TFEB nuclear translocation and lysosomal biogenesis to accelerate granulocytic differentiation in leukemia.\",\n      \"evidence\": \"RNAi FASN knockdown, EGCG treatment, TFEB translocation and CLEAR gene assays in APL cells\",\n      \"pmids\": [\"33742137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from FASN to TFEB activation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined opposing palmitoyltransferases that set FASN stability, with ZDHHC20 (C1471/C1881) blocking ubiquitination to stabilize FASN and ZDHHC21 (C1317) destabilizing it.\",\n      \"evidence\": \"ABE/LC-MS palmitoylation mapping, Co-IP, ubiquitination and half-life assays, site mutagenesis, ZDHHC20 KO mice; ZDHHC21 Co-IP/mutagenesis in DLBCL\",\n      \"pmids\": [\"39696259\", \"38195819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single enzyme family produces opposite stability outcomes mechanistically unresolved\", \"Context-dependence of ZDHHC choice unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed FASN-supplied palmitate controls antigen presentation, with FASN inhibition reducing MHC-I palmitoylation and DHHC3-mediated lysosomal degradation to boost surface MHC-I and T-cell killing.\",\n      \"evidence\": \"CRISPR FASN KO, FASN inhibitors, DHHC3-MHC-I Co-IP, palmitoylation assays, CD8 cytotoxicity, orthotopic model\",\n      \"pmids\": [\"38486485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct flux from FASN palmitate to MHC-I acylation not isotope-traced\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended FASN palmitate signaling to immune checkpoint control, showing FASN depletion abolishes PD-L1 palmitoylation and induction, sensitizing cancer cells to T-cell killing.\",\n      \"evidence\": \"CRISPR FASN KO, PD-L1 palmitoylation assays, real-time T-cell cytotoxicity, ETC analysis\",\n      \"pmids\": [\"39349429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation in this study\", \"Palmitoyltransferase for PD-L1 not identified here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed FASN palmitate stabilizes mutant p53, defining a route by which lipogenesis sustains gain-of-function oncogenic p53.\",\n      \"evidence\": \"FASN-mutp53 Co-IP, palmitoylation/ubiquitination assays, FASN inhibition across xenografts, transgenic mice, organoids\",\n      \"pmids\": [\"39971971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mutp53 palmitoylation site not mapped in this entry\", \"Whether wild-type p53 is similarly affected unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated FASN-derived malonyl-CoA negatively regulates innate immunity by inhibiting STING palmitoylation at C91, distinguishing malonyl-CoA from palmitate as a regulatory metabolite.\",\n      \"evidence\": \"Metabolomics, STING-KO mice, FASN inhibitors, STING C91 mutagenesis\",\n      \"pmids\": [\"38878833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which malonyl-CoA inhibits a palmitoyltransferase not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added VCP/USP2 as a FASN-stabilizing deubiquitination module that promotes autophagy and osteosarcoma progression, with the interaction interfaces mapped.\",\n      \"evidence\": \"Co-IP/MS, K48-ubiquitination assays, docking, truncation mapping, LC3/TEM autophagy readouts, xenografts\",\n      \"pmids\": [\"39489738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FASN deubiquitination site not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked FASN to ferroptosis and radioresistance via a GSTM3-USP14 axis that stabilizes FASN to sustain lipid synthesis.\",\n      \"evidence\": \"Co-IP/MS, ferroptosis markers, in vitro and xenograft radiosensitivity assays\",\n      \"pmids\": [\"38228715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct USP14-FASN deubiquitination not biochemically isolated from GSTM3-GPX4 effects\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected gut-microbial AhR signaling to FASN transcription, showing AhR activation lowers FASN and shifts the MUFA/PUFA ratio to sensitize cells to ferroptosis.\",\n      \"evidence\": \"AhR activation, FASN knockdown, lipid profiling, ferroptosis assays in vitro and in vivo\",\n      \"pmids\": [\"40557796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AhR occupancy of FASN promoter inferred not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated DPP3 in FASN protein stabilization to support breast cancer lipogenesis, though the mechanism of stabilization remains undefined.\",\n      \"evidence\": \"DPP3 KO, GSEA, FASN Western blot, free fatty acid metabolomics\",\n      \"pmids\": [\"38655619\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct DPP3-FASN binding or ubiquitination assay reported\", \"Stabilization inferred from KO plus Western blot only\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a non-metabolic structural role for FASN in late autophagy, showing FASN interacts with the SNARE machinery and is required for autophagosome-lysosome fusion.\",\n      \"evidence\": \"Co-IP/immunofluorescence of FASN with STX17/SNAP29/VAMP8, rescue, autophagy markers, TEM\",\n      \"pmids\": [\"38164137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FASN catalysis or scaffolding mediates fusion not separated\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined FASN's surfactant role, showing AEC2-specific Fasn deletion alters surfactant phospholipid composition and raises surface tension, worsening smoke-induced lung injury.\",\n      \"evidence\": \"AEC2-specific Fasn KO, BALF lipidomics, surface tension assay, lung histology\",\n      \"pmids\": [\"37606038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific FASN-derived phospholipid precursor not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the binding mode of clinical FASN inhibitors, showing TVB-3166/TVB-3664 act as uncompetitive inhibitors at the ketoacyl reductase domain toward NADPH, with NADPH accumulation tracking apoptotic sensitivity.\",\n      \"evidence\": \"Computational docking/kinetics, NADPH accumulation assays, BH3 profiling, PDX combination experiments\",\n      \"pmids\": [\"39999714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding mode is largely computational\", \"Crystallographic confirmation absent\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many FASN regulatory inputs — opposing palmitoyltransferases, multiple E3 ligases/DUBs, and transcriptional activators — are integrated in a given cell, and whether FASN's palmitate-donor, malonyl-CoA, and SNARE-scaffolding roles are catalytically separable, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of FASN protein-level regulation\", \"Flux tracing from FASN to specific substrate palmitoylation events lacking\", \"Scaffold vs catalytic contributions of FASN to autophagy not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 24, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 11, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FBXW7\", \"TRIM21\", \"USP13\", \"USP2\", \"ZDHHC20\", \"ZDHHC21\", \"FABP5\", \"STX17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}