{"gene":"FABP5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2014,"finding":"Crystal structure and biochemical analysis revealed that 'activating' polyunsaturated fatty acids (linoleic and arachidonic acid) induce FABP5 cytoplasmic-to-nuclear translocation by permitting allosteric communication between the ligand-sensing β2 loop and a tertiary nuclear localization signal within the α-helical cap. More saturated, non-activating fatty acids inhibit NLS formation by destabilizing the activation loop, implicating FABP5 specifically in cis-bonded polyunsaturated fatty acid signaling to PPARβ/δ.","method":"X-ray crystallography, HDX-MS, fluorescence anisotropy, nuclear translocation assays with linoleic acid vs. saturated fatty acids","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biochemical mutagenesis and translocation assays in a single rigorous study; establishes allosteric mechanism at atomic resolution","pmids":["24692551"],"is_preprint":false},{"year":2002,"finding":"NMR solution structure of human E-FABP determined, consisting of 10 anti-parallel β-strands forming a β-barrel. Backbone dynamics showed uniformly low mobility (average order parameter S²=0.88), distinct from heart-type FABP, with hydrogen-bond network stability correlating with conformational exchange on the millisecond-to-microsecond timescale.","method":"Multi-dimensional NMR spectroscopy, ¹⁵N relaxation experiments (T1, T2, heteronuclear NOE), hydrogen/deuterium exchange","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — full NMR structure determination with dynamic analysis using multiple complementary NMR methods in a single rigorous study","pmids":["12049637"],"is_preprint":false},{"year":2013,"finding":"FABP5 shuttles fatty acid ligands from the cytosol to the nuclear receptor PPARβ/δ, enhancing its transcriptional activity. Genetic ablation of FABP5 in MMTV-ErbB2/HER2 oncomice relieved activation of EGFR downstream effector signals, decreased expression of PPARδ target genes driving cell proliferation, and suppressed mammary tumor development, establishing FABP5 as essential for HER2-driven mammary tumorigenesis.","method":"Genetic knockout (FABP5-null × MMTV-ErbB2 mice), ectopic expression in 3T3 fibroblasts, PPARδ target gene expression, downstream signaling analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with two orthogonal model systems (KO mouse cross + ectopic expression), multiple phenotypic and molecular readouts","pmids":["23722546"],"is_preprint":false},{"year":2014,"finding":"FABP5 controls brain anandamide (AEA) disposition through two mechanisms: (1) it promotes hydrolysis of AEA into arachidonic acid (reducing endocannabinoid levels) and (2) it directly shuttles arachidonic acid to the nucleus where it delivers it to PPARβ/δ for activation. Ablation of FABP5 in mice causes excess AEA accumulation, abolishes PPARβ/δ activation in the brain, and markedly impairs hippocampus-based learning and memory.","method":"FABP5 knockout mice, AEA quantification, PPARβ/δ target gene expression, behavioral testing (hippocampus-dependent tasks)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO with multiple molecular and behavioral readouts establishing dual mechanistic role","pmids":["24644281"],"is_preprint":false},{"year":2021,"finding":"FABP5 is susceptible to S-glutathionylation at Cys127 under oxidative conditions. This modification promotes FABP5's fatty acid binding ability and nuclear translocation, and promotes interaction of FABP5 with PPARβ/δ, activating PPARβ/δ target genes and suppressing LPS-induced inflammation in macrophages. The deglutathionylation enzyme Grx1 reverses this modification.","method":"Quantitative redox proteomics, site-directed mutagenesis (Cys127), nuclear fractionation, co-immunoprecipitation of FABP5-PPARβ/δ, Grx1 KO and conditional KO mice (Grx1fl/flLysMcre)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — PTM identified by redox proteomics, validated by site-specific mutagenesis, functional consequences confirmed in vivo with conditional KO","pmids":["34876574"],"is_preprint":false},{"year":2010,"finding":"FABP5 regulates keratinocyte differentiation via 13(S)-HODE-mediated NF-κB activation. FABP5 facilitates incorporation of linoleic acid into cells; linoleic acid is then metabolized to 13(S)-HODE, which induces keratin 1 expression concomitant with increased NF-κB activity. E-FABP(-/-) keratinocytes show decreased 13(S)-HODE levels, reduced NF-κB activity, and decreased keratin 1 expression.","method":"E-FABP knockout mice, linoleic acid incorporation assays, 13(S)-HODE quantification, NF-κB reporter assays, keratinocyte differentiation markers","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined lipid metabolite (13(S)-HODE) as mechanistic intermediary and NF-κB as downstream effector, multiple orthogonal readouts","pmids":["21068754"],"is_preprint":false},{"year":2014,"finding":"E-FABP (FABP5) is highly expressed in macrophages and promotes antitumor activity by upregulating lipid droplet formation in response to tumors, leading to high IFN-β production. E-FABP-mediated IFN-β signaling enhances recruitment of NK cells to the tumor stroma.","method":"E-FABP KO mice, tumor-associated macrophage isolation, lipid droplet staining, IFN-β ELISA, NK cell recruitment assays, mammary tumor implantation model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular and molecular phenotype (IFN-β, lipid droplets, NK recruitment), single lab","pmids":["24713431"],"is_preprint":false},{"year":2020,"finding":"FABP5 is a binding partner of HIF-1α, identified by proteomics. FABP5 enhances HIF-1α activity by promoting HIF-1α synthesis while disrupting FIH/HIF-1α interaction. Oleic acid treatment activates the FABP5/HIF-1α axis, promoting lipid accumulation and cell proliferation in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation proteomics to identify HIF-1α binding partners, FABP5 knockdown/overexpression, HIF-1α translation assay, FIH competitive binding assay, lipid accumulation measurement","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP-based partner identification with functional follow-up showing disruption of FIH/HIF-1α interaction, single lab with multiple methods","pmids":["33128030"],"is_preprint":false},{"year":2019,"finding":"FABP5 acts as a central lipid chaperone linking cytosolic fatty acid metabolism (generated by FASN and MAGL) to pro-metastatic nuclear receptor signaling in prostate cancer. The pro-metastatic effects of FASN and MAGL are critically dependent on co-expression of FABP5 both in vitro and in vivo.","method":"ShRNA knockdown of FABP5, FASN, MAGL combinations; nuclear receptor activation assays; in vivo xenograft metastasis models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via combinatorial knockdown in vitro and in vivo, single lab","pmids":["31831821"],"is_preprint":false},{"year":2018,"finding":"FABP5 promotes lipolysis of lipid droplets, de novo fatty acid synthesis, and NF-κB signaling in cancer cells. FABP5 knockdown downregulates HSL, MAGL, Elovl6, and ACSL1. FABP5 activates NF-κB through reactive oxygen species and protein kinase C.","method":"siRNA knockdown in prostate and breast cancer cells, gene expression analysis, ROS measurement, PKC activity assays, NF-κB reporter assays","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with defined molecular pathway components, single lab, multiple readouts","pmids":["29906613"],"is_preprint":false},{"year":2022,"finding":"FABP5 selectively programs long-chain unsaturated fatty acid (particularly oleic acid) metabolism in macrophages. Fabp5 deletion causes accumulation of free long-chain unsaturated FAs; the mechanism involves enhanced FA β-oxidation, TCA cycle, and oxidative phosphorylation via activation of PPARγ signaling, reshaping macrophages toward M2 polarization.","method":"Myeloid-specific FABP5 conditional KO mice, OVA-induced allergic airway inflammation model, in vitro M2 polarization assays, lipidomics, metabolic flux analysis, PPARγ signaling readouts","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with lipidomics and metabolic pathway analysis, single lab with multiple orthogonal methods","pmids":["36384126"],"is_preprint":false},{"year":2022,"finding":"FABP5 deletion in macrophages increases intracellular unsaturated fatty acids (especially oleic acid), which increases the AMP/ATP ratio and activates AMPK, thereby inhibiting the NF-κB pathway and reducing macrophage inflammatory responses. Pharmacological AMPK inhibition rescued the decreased NF-κB signaling in FABP5-KO macrophages.","method":"Myeloid-specific FABP5 KO mice, LPS-induced acute liver injury model, RNA-sequencing, AMP/ATP ratio measurement, AMPK activation assays, NF-κB pathway analysis, pharmacological rescue with AMPK inhibitor","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with RNA-seq pathway analysis and pharmacological rescue establishing AMPK-NF-κB axis, single lab","pmids":["36426981"],"is_preprint":false},{"year":2025,"finding":"FABP5 directly binds to Raptor (the regulatory-associated protein of mTOR) to enhance formation of functional mTORC1 and substrate binding, activated by ω-6 linoleic acid. This constitutes a direct nutrient-sensing mechanism linking dietary linoleic acid to mTORC1 activation and cell proliferation.","method":"Co-immunoprecipitation of FABP5-Raptor, in vitro binding assays, mTORC1 activity assays, FABP5 KO cells, FABP5-linoleic acid binding assessment","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein-protein interaction (FABP5-Raptor) validated by Co-IP with functional mTORC1 reconstitution and loss-of-function, published in high-profile journal with multiple orthogonal methods","pmids":["40080571"],"is_preprint":false},{"year":2022,"finding":"Activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis in an FABP5-dependent manner. Mechanistically, FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Keratinocyte-specific (Krt6a-Cre) but not myeloid-specific (LysM-Cre) FABP5 deletion attenuates psoriatic symptoms.","method":"Global and conditional KO mice (Krt6a-Cre, LysM-Cre), proteomic analysis identifying FABP5-VCP interaction, Co-IP, siRNA silencing of FABP5 and VCP, NF-κB reporter assays, neutrophil chemotaxis assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO epistasis combined with proteomic identification of binding partner (VCP), Co-IP validation, and signaling pathway analysis with multiple orthogonal methods","pmids":["37967009"],"is_preprint":false},{"year":2024,"finding":"Long-chain unsaturated fatty acids (UFAs) released by tumor cells activate PPARγ via FABP5 in tumor-associated macrophages (TAMs), resulting in immunosuppressive properties. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression and enhances T cell-dependent antitumor immunity.","method":"Macrophage-specific FABP5 KO mice, single-cell RNA sequencing, in vitro UFA stimulation of macrophages, PPARγ signaling readouts, tumor growth assays","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with single-cell transcriptomics and PPARγ mechanistic validation, single lab","pmids":["39357545"],"is_preprint":false},{"year":2017,"finding":"FABP5 overexpression in human fibroblasts causes nuclear translocation of SMAD2 and significant activation of the TGF-β signaling pathway, promoting profibrotic gene expression. Exogenous FABP5-EGFP can be incorporated by skin cells and intensify TGF-β signaling.","method":"FABP5 overexpression in WS1 fibroblasts, immunofluorescence of SMAD2 nuclear localization, TGF-β target gene expression, exogenous FABP5-EGFP uptake","journal":"Radiation research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with defined signaling readout (SMAD2 nuclear translocation) and exogenous protein uptake demonstrated, single lab","pmids":["29215326"],"is_preprint":false},{"year":2015,"finding":"FABP5 overexpression in prostate cancer is caused by hypomethylation of a CpG island in its promoter region, coupled with upregulation of direct trans-acting transcription factors Sp1 and c-Myc. Silencing Sp1, c-Myc, or FABP5 significantly decreases cancer cell proliferation.","method":"Bisulfite sequencing, COBRA, qAMP methylation analysis; Sp1 and c-Myc siRNA knockdown; proliferation assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epigenetic mechanism defined by bisulfite sequencing with functional validation via transcription factor knockdown, single lab","pmids":["26614767"],"is_preprint":false},{"year":2013,"finding":"E-FABP (FABP5) induces differentiation markers (K10, involucrin) in normal human keratinocytes. E-FABP inhibition by siRNA downregulates K10 and involucrin through NF-κB and JNK signaling pathways.","method":"Recombinant E-FABP transfection, siRNA knockdown, differentiation marker expression (K10, involucrin), NF-κB and JNK pathway assays","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — bidirectional (gain and loss of function) with defined pathway readouts (NF-κB, JNK), single lab","pmids":["23528210"],"is_preprint":false},{"year":2008,"finding":"E-FABP binds a broad range of saturated and unsaturated long-chain fatty acids including DHA, EPA, and arachidonic acid. E-FABP expression is required for normal neurite extension in NGF-differentiated PC12 cells; antisense knockdown reduces neurite number/length, and replenishment with recombinant E-FABP restores neurite outgrowth. E-FABP localizes to cytoplasm and nuclear regions of neurons.","method":"FABP radiobinding analysis, antisense PC12 clones, recombinant E-FABP protein rescue, neurite measurement, subcellular fractionation/immunofluorescence","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — antisense knockdown plus recombinant protein rescue with defined cellular phenotype, single lab","pmids":["18513372"],"is_preprint":false},{"year":2014,"finding":"FABP5 promotes intracellular transport and inactivation of endocannabinoids (including anandamide) in intestinal K cells. FABP5-deficient mice have significantly decreased circulating GIP levels in the fasting state and in response to acute oral fat diet administration, establishing FABP5 as a regulator of GIP secretion via endocannabinoid control.","method":"FABP5-KO mice, GIP-GFP reporter knock-in mice, RNA-seq of purified K cells, GIP ELISA from plasma after fat challenge","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined hormonal phenotype (GIP) and mechanistic link (endocannabinoid transport), single lab","pmids":["25268051"],"is_preprint":false},{"year":2022,"finding":"FABP5 deletion specifically in TRPV1+ nociceptors augments anandamide levels, producing antinociceptive effects mediated by CB1. Mechanistically, FABP5 deletion suppresses inflammation- and NGF-mediated TRPV1 sensitization via CB1 through calcineurin. FABP5 functions as an intracellular AEA carrier to FAAH for inactivation in nociceptors.","method":"Conditional FABP5 KO (TRPV1-Cre), anandamide quantification, TRPV1 sensitization assays (capsaicin, NGF), CB1 antagonist pharmacology, calcineurin inhibitor studies, FAAH inhibitor comparison","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with pharmacological dissection of CB1/calcineurin mechanism and comparison with FAAH inhibition, multiple orthogonal readouts","pmids":["35655086"],"is_preprint":false},{"year":1999,"finding":"E-FABP (FABP5) and S100A7 form a complex in the cytosol of human keratinocytes. Gel filtration and non-denaturing PAGE showed S100A7 co-purifies with E-FABP; co-immunoprecipitation confirmed their association in protein extracts from psoriatic scales.","method":"Gel filtration chromatography, non-denaturing PAGE, co-immunoprecipitation from psoriatic keratinocyte extracts","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-purification and co-IP with two orthogonal native methods, single lab","pmids":["10331666"],"is_preprint":false},{"year":2009,"finding":"FABP5 knockdown in RPE cells decreases cholesterol and cholesterol ester levels by ~40%, increases triglycerides by 67%, and decreases apoB100 secretion by 76%, demonstrating that FABP5 plays a critical role in lipid metabolism and lipoprotein particle formation in retinal pigment epithelial cells.","method":"siRNA knockdown in ARPE-19 cells, lipid class quantification, apoB100 ELISA, lipoprotein secretion assay","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA knockdown with multiple quantitative lipid and lipoprotein readouts, single lab","pmids":["19434059"],"is_preprint":false},{"year":2012,"finding":"Both FABP7 and FABP5 are required for normal proliferation and differentiation of neural stem/progenitor cells in the postnatal hippocampal dentate gyrus. FABP5 KO reduces the number of mature oligodendrocytes with membrane sheet morphology, and FABP7/FABP5 double KO dramatically reduces NSC/NPC numbers while increasing survival of BrdU+ cells and enhancing neuronal differentiation.","method":"Single and double FABP KO mice, BrdU incorporation and survival tracking, immunofluorescent staging of NSC/NPC differentiation markers","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with cell-type-specific phenotypic readouts and epistasis between FABP7 and FABP5, single lab","pmids":["22581784"],"is_preprint":false},{"year":2002,"finding":"E-FABP KO mice show impaired recovery of transepidermal water loss (TEWL) after skin lipid barrier disruption by acetone, with lower basal TEWL. H-FABP expression is specifically elevated in liver of neonatal heterozygous and homozygous mice, suggesting functional compensation by H-FABP for E-FABP deficiency.","method":"E-FABP KO mice, TEWL measurement after acetone treatment, Northern blot for compensatory FABP expression","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined functional phenotype (TEWL) and compensatory mechanism (H-FABP upregulation), single lab","pmids":["12479572"],"is_preprint":false},{"year":2021,"finding":"FABP5 co-localizes with α-synuclein (αSyn) in mitochondria under oxidative stress (rotenone treatment), reducing mitochondrial membrane potential and promoting cell death. Pharmacological inhibition of FABP5 prevented αSyn accumulation in mitochondria and rescued cell viability.","method":"Co-overexpression of FABP5 and αSyn in Neuro-2A cells, rotenone treatment, co-localization immunofluorescence, mitochondrial membrane potential assay, FABP5 pharmacological inhibitor rescue","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization with mitochondrial functional readout and pharmacological rescue, single lab","pmids":["33499263"],"is_preprint":false},{"year":2019,"finding":"Palmitate acid promotes nuclear transport of FABP5, which then increases nuclear SP1 protein levels, consequently increasing UCA1 expression in gastric cancer cells and promoting metastatic properties.","method":"Immunofluorescence of FABP5 nuclear translocation after PA treatment, siRNA knockdown of FABP5 and SP1, Western blot, RT-PCR for UCA1, migration/invasion assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ligand-induced nuclear translocation with downstream transcription factor (SP1) and target (UCA1) validated by siRNA, single lab","pmids":["30948929"],"is_preprint":false},{"year":2013,"finding":"FABP5 modulates PPARγ activity in airway epithelial cells; FABP5 overexpression increases expression of β-defensin-2 and limits IL-8 production against Pseudomonas aeruginosa infection. FABP5 knockdown increases bacterial load and inflammatory cytokine production. FABP5 exerts protective immunomodulatory functions through modulation of PPARγ activity.","method":"FABP5 knockdown and overexpression in primary NHBE cells, P. aeruginosa infection assay, β-defensin-2 and IL-8 quantification, PPARγ activity assay, cigarette smoke exposure","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — bidirectional expression manipulation with defined antimicrobial and inflammatory readouts and PPARγ pathway link, single lab","pmids":["23349676"],"is_preprint":false},{"year":2021,"finding":"FABP5 deficiency in cardiac fibroblasts increases oxidative stress, reduces mitochondrial respiration, and increases myofibroblast activation markers in response to TGF-β. In FABP5 KO mice with TAC-induced cardiac remodeling, FABP5 deficiency aggravates cardiac hypertrophy, fibrosis, and mitochondrial impairment.","method":"FABP5 global KO mice with TAC surgery, echocardiography, transmission electron microscopy, ATP detection, siRNA in primary cardiac fibroblasts, mitochondrial respiration assay, oxidative stress assay","journal":"Cardiovascular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model combined with in vitro siRNA mechanistic analysis of mitochondrial function, single lab","pmids":["33929718"],"is_preprint":false},{"year":2010,"finding":"FABP5 knockdown in 3T3-L1 preadipocytes during adipocytic induction triggers apoptosis via caspase-3 activation and reduces expression of PPARγ and C/EBPα. FABP5 is required for preadipocyte viability during adipogenesis through activation of the Akt cascade.","method":"siRNA knockdown in 3T3-L1 cells during adipogenic induction, caspase-3 activity assay, procaspase-3 cleavage, PPARγ/C/EBPα Western blot, Akt phosphorylation assay","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA knockdown with defined apoptotic and signaling readouts, single lab","pmids":["20238174"],"is_preprint":false},{"year":2024,"finding":"MELK kinase binds to FABP5 and stabilizes it by affecting its ubiquitination through the K48R pathway, thereby activating the Akt/mTOR signaling axis in HCC cells.","method":"Co-immunoprecipitation of MELK-FABP5, ubiquitination assay identifying K48-linked ubiquitin chain modification, Akt/mTOR pathway readouts, MELK knockdown","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with ubiquitination type characterized and downstream signaling validated, single lab","pmids":["39871325"],"is_preprint":false},{"year":2024,"finding":"TRIM45 E3 ligase directly adds K33-type and K63-type poly-ubiquitin chains to the NLS domain of FABP5, promoting FABP5 nuclear translocation. Nuclear FABP5 then interacts with PPARγ to facilitate downstream lipid synthesis gene expression.","method":"IP-tandem mass spectrometry identifying TRIM45-FABP5 interaction, ubiquitin linkage-specific assay (K33/K63), nuclear fractionation, FABP5-PPARγ Co-IP, gene expression of lipid synthesis targets","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified ubiquitination with linkage specificity, nuclear translocation validated, PPARγ interaction confirmed by Co-IP, single lab","pmids":["38755308"],"is_preprint":false},{"year":2025,"finding":"Asprosin interacts with FABP5, and this interaction facilitates abnormal nuclear localization of asprosin. Nuclear asprosin directly binds to and inhibits PPARα transcriptional activity at PPRE elements, disrupting hepatic fatty acid β-oxidation. GalNAc-siRNA targeting hepatic FABP5 ameliorates hepatic steatosis in MASLD.","method":"Co-IP of asprosin-FABP5, nuclear fractionation, PPRE reporter assay, ChIP for asprosin at PPREs, hepatocyte-specific asprosin overexpression/knockdown, GalNAc-siRNA targeting FABP5","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with nuclear localization mechanism validated by ChIP and reporter assay, in vivo GalNAc-siRNA intervention, single lab","pmids":["40231957"],"is_preprint":false},{"year":2023,"finding":"FABP5 interacts with fatty acid synthase (FASN) and promotes FASN degradation through the ubiquitin proteasome pathway, leading to decreased FASN expression, reduced lipid accumulation, and suppression of mTOR signaling to facilitate autophagy in colorectal cancer cells.","method":"Co-immunoprecipitation of FABP5-FASN, ubiquitin proteasome pathway assay, mTOR signaling readouts, autophagy assays, FABP5 KO/overexpression in CRC cells","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with proteasome pathway validation and defined signaling outcome, single lab","pmids":["37416772"],"is_preprint":false},{"year":2023,"finding":"FABP5 interacts with FASN in pancreatic neuroendocrine neoplasm cells and regulates FASN expression via the ubiquitin proteasome pathway. FABP5 promotes lipid droplet deposition and activates the WNT/β-catenin signaling pathway to facilitate pNEN progression.","method":"Co-immunoprecipitation of FABP5-FASN, ubiquitin proteasome pathway assay, lipid droplet staining, WNT/β-catenin reporter assays, FABP5 knockdown/overexpression","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with proteasome validation and WNT/β-catenin pathway link, single lab","pmids":["37302809"],"is_preprint":false},{"year":2022,"finding":"FABP5 in macrophage monocytes activates FABP5 expression and decreases β-oxidation, causing lipid droplet accumulation. This FABP5-mediated lipid accumulation increases IL-10 secretion by suppressing the PPARα pathway. The elevated IL-10 then promotes PD-L1 expression on Treg cells via JNK-STAT3 pathway activation, fostering immune tolerance in HCC.","method":"FABP5 knockdown in monocytes, β-oxidation assay, lipid droplet staining, IL-10 ELISA, PPARα pathway analysis, PD-L1 expression on Tregs, JNK-STAT3 signaling","journal":"Cancer gene therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — individual pathway components shown but mechanistic chain from FABP5-lipid accumulation to PPARα to IL-10 to JNK-STAT3-PD-L1 relies on multiple inferential steps, single lab","pmids":["35902729"],"is_preprint":false},{"year":2021,"finding":"E-FABP (FABP5) expressed in T cells facilitates linoleic acid (LA) mitochondrial transport and cardiolipin incorporation. LA induces mitochondrial ROS production and lipid peroxidation in T cells; E-FABP genetic depletion rescues LA-impaired T-cell responses and suppresses LA-rich HFD-associated mammary tumor growth.","method":"E-FABP KO mice on high-fat diet, LA/OA fatty acid uptake comparison, mitochondrial ROS measurement, cardiolipin incorporation assay, T cell apoptosis and TNFα production assays, tumor growth","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined lipid transport mechanism (cardiolipin incorporation) and mitochondrial ROS readout, single lab with in vivo confirmation","pmids":["34400394"],"is_preprint":false},{"year":2025,"finding":"GPR171 deficiency promotes Th17 cell differentiation and alters lipidome via the cAMP-pCREB-FABP5 axis. Blockade of FABP5 reduces Th17 cell differentiation in vitro and ameliorates DSS-induced colitis in Gpr171-/- mice, placing FABP5 downstream of GPR171/cAMP/pCREB in Th17 differentiation.","method":"GPR171 KO mice, BigLEN ligand treatment, cAMP/pCREB pathway analysis, FABP5 inhibitor treatment, RNA-seq, lipidomics, DSS colitis model with Gpr171-/- background","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (GPR171 KO rescued by FABP5 inhibitor) with defined signaling axis, single lab","pmids":["40074327"],"is_preprint":false},{"year":2019,"finding":"Lysine enhances fatty acid-stimulated milk fat synthesis through GPRC6A-PI3K-FABP5 signaling in bovine mammary epithelial cells. Lysine stimulates FABP5 expression via GPRC6A-PI3K signaling, and FABP5 in turn enhances SREBP-1c expression and maturation to drive milk fat synthesis.","method":"siRNA knockdown of FABP5 and GPRC6A, PI3K inhibitor treatment, SREBP-1c maturation assay, lipid droplet/milk fat quantification in BMECs","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA epistasis at multiple pathway nodes with functional metabolic readout, single lab","pmids":["31174423"],"is_preprint":false},{"year":2024,"finding":"The FABP5 inhibitor ART26.12 selectively binds FABP5 compared to FABP3, FABP4, and FABP7, and produces CB1-dependent anti-allodynic effects in an oxaliplatin-induced peripheral neuropathy model; spinal cord lipidomics revealed widespread lipid modulation including N-acyl amino acids.","method":"Binding selectivity (MST/fluorescence), CB1 antagonist pharmacology, OIPN mouse model with acute and repeated dosing, multi-scale lipidomics of spinal cord","journal":"The journal of pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological selectivity profiling plus CB1 pharmacological epistasis in in vivo pain model with lipidomics, single lab","pmids":["38232863"],"is_preprint":false},{"year":2024,"finding":"Fatty acid binding properties of FABP5 characterized by EPR spectroscopy: FABP5 shows two distinct binding states ('intermediately' and 'strongly' bound) for fatty acid ligands; the proportion and dynamics of binding depend on FABP concentration and temperature, with the more dynamic 'intermediately bound' state dominating at body temperature.","method":"CW-EPR spectroscopy with spin-labeled fatty acids (5/16-DOXYL stearic acid), microscale thermophoresis, dynamic light scattering, EPR spectral simulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biophysical characterization of ligand binding states using EPR, single lab, no mutagenesis or functional validation","pmids":["38777142"],"is_preprint":false}],"current_model":"FABP5 is an intracellular lipid chaperone that binds long-chain (particularly polyunsaturated) fatty acids and endocannabinoids within a β-barrel structure; specific polyunsaturated fatty acids allosterically expose a nuclear localization signal in the α-helical cap, driving cytoplasm-to-nucleus translocation where FABP5 delivers ligands to activate PPARβ/δ or PPARγ and regulate gene transcription. FABP5 also transports anandamide to FAAH for inactivation (modulating endocannabinoid and CB1 signaling), directly binds Raptor to activate mTORC1 in response to ω-6 linoleic acid, interacts with binding partners including VCP (activating NF-κB), HIF-1α (promoting its synthesis), FASN (regulating its ubiquitin-proteasome degradation), and asprosin (enabling its nuclear localization to inhibit PPARα). Post-translational regulation includes S-glutathionylation at Cys127 (promoting nuclear translocation and PPARβ/δ interaction), K33/K63-ubiquitination by TRIM45 at the NLS domain (promoting nuclear translocation), and K48-linked ubiquitin stabilization by MELK. In immune cells, FABP5 governs fatty acid oxidation, macrophage polarization, and T cell function, while in keratinocytes it promotes differentiation and NF-κB-mediated neutrophil recruitment."},"narrative":{"mechanistic_narrative":"FABP5 (epidermal fatty acid-binding protein) is an intracellular lipid chaperone that binds long-chain saturated and unsaturated fatty acids — including arachidonic, linoleic, and docosahexaenoic acids — within a β-barrel of ten anti-parallel β-strands, coupling cytosolic lipid metabolism to nuclear and signaling outputs [PMID:12049637, PMID:18513372, PMID:38777142]. Its central regulatory feature is ligand-gated nuclear import: 'activating' cis-bonded polyunsaturated fatty acids permit allosteric communication between the β2 ligand-sensing loop and a tertiary nuclear localization signal in the α-helical cap, driving cytoplasm-to-nucleus translocation, whereas saturated fatty acids destabilize this activation loop [PMID:24692551]. Once nuclear, FABP5 delivers fatty acid ligands to PPARβ/δ and PPARγ to potentiate their transcriptional activity, a function essential for HER2-driven mammary tumorigenesis and for shuttling arachidonic acid to PPARβ/δ in brain to support hippocampal learning [PMID:23722546, PMID:24644281, PMID:39357545]. FABP5 simultaneously governs endocannabinoid disposition by carrying anandamide to FAAH for hydrolysis, modulating CB1 signaling in nociceptors and controlling GIP secretion in intestinal K cells [PMID:24644281, PMID:25268051, PMID:35655086]. Beyond nuclear receptors, FABP5 directly binds Raptor to assemble functional mTORC1 in response to ω-6 linoleic acid, and engages additional partners — VCP to drive NF-κB-dependent neutrophil recruitment, HIF-1α to enhance its synthesis, FASN to direct its proteasomal degradation, and asprosin to enable nuclear inhibition of PPARα [PMID:40080571, PMID:37967009, PMID:33128030, PMID:37416772, PMID:40231957]. In immune cells FABP5 programs long-chain unsaturated fatty acid metabolism, fatty acid β-oxidation, and macrophage M2/immunosuppressive polarization, and shapes T cell and Th17 responses [PMID:36384126, PMID:39357545, PMID:34400394, PMID:40074327]; in keratinocytes it promotes differentiation through 13(S)-HODE-driven NF-κB signaling [PMID:21068754, PMID:23528210]. Its activity is tuned post-translationally by S-glutathionylation at Cys127 and by ubiquitination of the NLS domain by TRIM45 (K33/K63) or stabilization via MELK (K48), all of which favor nuclear translocation and PPAR engagement [PMID:34876574, PMID:38755308, PMID:39871325].","teleology":[{"year":2002,"claim":"Establishing the three-dimensional fold and dynamics of FABP5 was the prerequisite for understanding how it sequesters and releases lipid ligands.","evidence":"Multidimensional NMR structure determination with 15N relaxation and H/D exchange of human E-FABP","pmids":["12049637"],"confidence":"High","gaps":["Did not define ligand-bound conformational changes","No link between dynamics and nuclear translocation yet"]},{"year":2008,"claim":"Defining FABP5's ligand spectrum and a cellular requirement showed it is a broad long-chain fatty acid carrier with functional consequences in neurons.","evidence":"Radiobinding analysis plus antisense knockdown and recombinant protein rescue in NGF-differentiated PC12 cells","pmids":["18513372"],"confidence":"Medium","gaps":["Did not resolve molecular downstream effector for neurite outgrowth","Nuclear vs cytoplasmic roles not separated"]},{"year":2013,"claim":"Genetic epistasis established FABP5 as the lipid-delivery arm of PPARβ/δ transcriptional signaling driving proliferation.","evidence":"FABP5-null × MMTV-ErbB2 mouse cross plus ectopic expression with PPARδ target gene readouts","pmids":["23722546"],"confidence":"High","gaps":["Identity of the operative endogenous ligand not pinned down","Mechanism of nuclear import not yet structural"]},{"year":2014,"claim":"A crystal structure resolved how specific polyunsaturated fatty acids allosterically expose the NLS, providing the atomic basis for ligand-selective nuclear translocation.","evidence":"X-ray crystallography, HDX-MS, fluorescence anisotropy and translocation assays comparing linoleic/arachidonic vs saturated fatty acids","pmids":["24692551"],"confidence":"High","gaps":["Did not capture the nuclear receptor handoff structurally","Cellular ligand-sensing kinetics not measured"]},{"year":2014,"claim":"Knockout studies revealed a dual role in endocannabinoid biology — FABP5 both promotes anandamide hydrolysis and delivers arachidonic acid to nuclear PPARβ/δ — linking it to learning and hormone secretion.","evidence":"FABP5-KO mice with AEA quantification, PPARβ/δ target genes, behavioral testing, and GIP reporter knock-in mice","pmids":["24644281","25268051"],"confidence":"High","gaps":["Relative flux to FAAH vs nucleus in vivo unquantified","Tissue-specific partitioning of the two functions unresolved"]},{"year":2010,"claim":"Defined a lipid-metabolite pathway whereby FABP5 channels linoleic acid to 13(S)-HODE to activate NF-κB and drive keratinocyte differentiation.","evidence":"E-FABP KO keratinocytes with linoleic acid incorporation, 13(S)-HODE quantification, NF-κB reporters and differentiation markers","pmids":["21068754","23528210"],"confidence":"High","gaps":["Mechanism by which FABP5 enhances LA incorporation unresolved","Direct vs indirect role in NF-κB activation not separated"]},{"year":2021,"claim":"Identifying S-glutathionylation at Cys127 showed redox state directly gates FABP5 nuclear translocation and PPARβ/δ engagement, tying oxidative signaling to its activity.","evidence":"Redox proteomics, Cys127 mutagenesis, nuclear fractionation, FABP5-PPARβ/δ Co-IP, Grx1 conditional KO mice","pmids":["34876574"],"confidence":"High","gaps":["Structural effect of Cys127 modification on NLS not solved","Crosstalk with ligand-induced translocation unclear"]},{"year":2022,"claim":"Conditional and tissue-specific knockouts established FABP5 as a programmer of immune cell lipid metabolism, controlling macrophage polarization and inflammatory tone through PPARγ, AMPK and NF-κB.","evidence":"Myeloid- and keratinocyte-specific KO mice with lipidomics, metabolic flux, AMPK/NF-κB analysis, and VCP partner identification in psoriasis models","pmids":["36384126","36426981","37967009"],"confidence":"High","gaps":["Whether PPARγ, AMPK and VCP routes operate in parallel or sequentially unresolved","Direct ligand sensed in each immune context not defined"]},{"year":2024,"claim":"Discovery of NLS-domain ubiquitination by TRIM45 and K48 stabilization by MELK added a ubiquitin-code layer controlling FABP5 nuclear translocation and stability.","evidence":"IP-MS, linkage-specific ubiquitination assays (K33/K63 and K48R), nuclear fractionation, FABP5-PPARγ Co-IP and Akt/mTOR readouts","pmids":["38755308","39871325"],"confidence":"Medium","gaps":["Interplay between ubiquitination and glutathionylation not tested","Deubiquitinases not identified"]},{"year":2025,"claim":"Direct binding to Raptor revealed a nuclear-receptor-independent function — FABP5 acts as a linoleic acid sensor that assembles functional mTORC1.","evidence":"Co-IP of FABP5-Raptor, in vitro binding, mTORC1 activity assays in FABP5-KO cells with linoleic acid","pmids":["40080571"],"confidence":"High","gaps":["Structural basis of the FABP5-Raptor interface unknown","Whether ligand binding modulates Raptor engagement unresolved"]},{"year":2025,"claim":"FABP5 was shown to carry asprosin into the nucleus to inhibit PPARα, extending its chaperone role to a protein cargo with metabolic-disease consequences.","evidence":"Asprosin-FABP5 Co-IP, nuclear fractionation, PPRE ChIP/reporter assays, and hepatic GalNAc-siRNA in a MASLD model","pmids":["40231957"],"confidence":"Medium","gaps":["Whether asprosin uses the lipid-gated NLS mechanism unknown","Single-lab finding without independent replication"]},{"year":null,"claim":"How the multiple competing inputs — ligand identity, Cys127 redox state, TRIM45/MELK ubiquitination, and protein partners (Raptor, VCP, HIF-1α, FASN, asprosin) — are integrated to determine FABP5 localization and which output pathway is engaged in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling cytoplasmic Raptor binding vs nuclear PPAR delivery","Quantitative hierarchy of PTMs and partners untested","Structural basis for most protein-protein interactions absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,18,40]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3,19,20,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,12,32]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,31]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,31,26]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[25,36]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,31]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,10,22,36]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,10,14,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[30,31,33]}],"complexes":["mTORC1"],"partners":["PPARD","PPARG","RPTOR","VCP","HIF1A","FASN","S100A7","TRIM45"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01469","full_name":"Fatty acid-binding protein 5","aliases":["Epidermal-type fatty acid-binding protein","E-FABP","Fatty acid-binding protein, epidermal","Psoriasis-associated fatty acid-binding protein homolog","PA-FABP"],"length_aa":135,"mass_kda":15.2,"function":"Intracellular carrier for long-chain fatty acids and related active lipids, such as endocannabinoids, that regulate the metabolism and actions of the ligands they bind. In addition to the cytosolic transport, selectively delivers specific fatty acids from the cytosol to the nucleus, wherein they activate nuclear receptors (PubMed:21395585, PubMed:22170058). Delivers retinoic acid to the nuclear receptor peroxisome proliferator-activated receptor delta; which promotes proliferation and survival. May also serve as a synaptic carrier of endocannabinoid at central synapses and thus controls retrograde endocannabinoid signaling. Modulates inflammation by regulating PTGES induction via NF-kappa-B activation, and prostaglandin E2 (PGE2) biosynthesis during inflammation (By similarity). May be involved in keratinocyte differentiation (PubMed:8092987)","subcellular_location":"Cytoplasm; Nucleus; Synapse; Postsynaptic density; Secreted","url":"https://www.uniprot.org/uniprotkb/Q01469/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FABP5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":5,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FABP5","total_profiled":1310},"omim":[{"mim_id":"618923","title":"FATTY ACID-BINDING PROTEIN 12; FABP12","url":"https://www.omim.org/entry/618923"},{"mim_id":"605168","title":"FATTY ACID-BINDING PROTEIN 5; FABP5","url":"https://www.omim.org/entry/605168"},{"mim_id":"604634","title":"TRANSGELIN 2; TAGLN2","url":"https://www.omim.org/entry/604634"},{"mim_id":"602965","title":"FATTY ACID-BINDING PROTEIN 7; FABP7","url":"https://www.omim.org/entry/602965"},{"mim_id":"600434","title":"FATTY ACID-BINDING PROTEIN 4; FABP4","url":"https://www.omim.org/entry/600434"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"cervix","ntpm":2768.1},{"tissue":"esophagus","ntpm":4866.2},{"tissue":"vagina","ntpm":3490.8}],"url":"https://www.proteinatlas.org/search/FABP5"},"hgnc":{"alias_symbol":["E-FABP","PA-FABP","KFABP"],"prev_symbol":[]},"alphafold":{"accession":"Q01469","domains":[{"cath_id":"2.40.128.20","chopping":"3-130","consensus_level":"high","plddt":96.6513,"start":3,"end":130}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01469","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01469-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01469-F1-predicted_aligned_error_v6.png","plddt_mean":96.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FABP5","jax_strain_url":"https://www.jax.org/strain/search?query=FABP5"},"sequence":{"accession":"Q01469","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01469.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01469/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01469"}},"corpus_meta":[{"pmid":"1512466","id":"PMC_1512466","title":"Molecular cloning and expression of a novel keratinocyte protein (psoriasis-associated fatty acid-binding protein [PA-FABP]) that is highly up-regulated in psoriatic skin and that shares similarity to fatty acid-binding proteins.","date":"1992","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/1512466","citation_count":225,"is_preprint":false},{"pmid":"28132904","id":"PMC_28132904","title":"Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases.","date":"2017","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28132904","citation_count":199,"is_preprint":false},{"pmid":"33128030","id":"PMC_33128030","title":"Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33128030","citation_count":194,"is_preprint":false},{"pmid":"34876574","id":"PMC_34876574","title":"Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34876574","citation_count":153,"is_preprint":false},{"pmid":"32550890","id":"PMC_32550890","title":"FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32550890","citation_count":143,"is_preprint":false},{"pmid":"24713431","id":"PMC_24713431","title":"Fatty acid-binding protein E-FABP restricts tumor growth by promoting IFN-β responses in tumor-associated macrophages.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24713431","citation_count":115,"is_preprint":false},{"pmid":"24692551","id":"PMC_24692551","title":"Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor β/δ (FABP5-PPARβ/δ) signaling pathway.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24692551","citation_count":104,"is_preprint":false},{"pmid":"29906613","id":"PMC_29906613","title":"Fatty acid-binding protein 5 (FABP5) promotes lipolysis of lipid droplets, de novo fatty acid (FA) synthesis and activation of nuclear factor-kappa B (NF-κB) signaling in cancer cells.","date":"2018","source":"Biochimica et biophysica acta. 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More saturated, non-activating fatty acids inhibit NLS formation by destabilizing the activation loop, implicating FABP5 specifically in cis-bonded polyunsaturated fatty acid signaling to PPARβ/δ.\",\n      \"method\": \"X-ray crystallography, HDX-MS, fluorescence anisotropy, nuclear translocation assays with linoleic acid vs. saturated fatty acids\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biochemical mutagenesis and translocation assays in a single rigorous study; establishes allosteric mechanism at atomic resolution\",\n      \"pmids\": [\"24692551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NMR solution structure of human E-FABP determined, consisting of 10 anti-parallel β-strands forming a β-barrel. Backbone dynamics showed uniformly low mobility (average order parameter S²=0.88), distinct from heart-type FABP, with hydrogen-bond network stability correlating with conformational exchange on the millisecond-to-microsecond timescale.\",\n      \"method\": \"Multi-dimensional NMR spectroscopy, ¹⁵N relaxation experiments (T1, T2, heteronuclear NOE), hydrogen/deuterium exchange\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full NMR structure determination with dynamic analysis using multiple complementary NMR methods in a single rigorous study\",\n      \"pmids\": [\"12049637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FABP5 shuttles fatty acid ligands from the cytosol to the nuclear receptor PPARβ/δ, enhancing its transcriptional activity. Genetic ablation of FABP5 in MMTV-ErbB2/HER2 oncomice relieved activation of EGFR downstream effector signals, decreased expression of PPARδ target genes driving cell proliferation, and suppressed mammary tumor development, establishing FABP5 as essential for HER2-driven mammary tumorigenesis.\",\n      \"method\": \"Genetic knockout (FABP5-null × MMTV-ErbB2 mice), ectopic expression in 3T3 fibroblasts, PPARδ target gene expression, downstream signaling analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with two orthogonal model systems (KO mouse cross + ectopic expression), multiple phenotypic and molecular readouts\",\n      \"pmids\": [\"23722546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FABP5 controls brain anandamide (AEA) disposition through two mechanisms: (1) it promotes hydrolysis of AEA into arachidonic acid (reducing endocannabinoid levels) and (2) it directly shuttles arachidonic acid to the nucleus where it delivers it to PPARβ/δ for activation. Ablation of FABP5 in mice causes excess AEA accumulation, abolishes PPARβ/δ activation in the brain, and markedly impairs hippocampus-based learning and memory.\",\n      \"method\": \"FABP5 knockout mice, AEA quantification, PPARβ/δ target gene expression, behavioral testing (hippocampus-dependent tasks)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO with multiple molecular and behavioral readouts establishing dual mechanistic role\",\n      \"pmids\": [\"24644281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FABP5 is susceptible to S-glutathionylation at Cys127 under oxidative conditions. This modification promotes FABP5's fatty acid binding ability and nuclear translocation, and promotes interaction of FABP5 with PPARβ/δ, activating PPARβ/δ target genes and suppressing LPS-induced inflammation in macrophages. The deglutathionylation enzyme Grx1 reverses this modification.\",\n      \"method\": \"Quantitative redox proteomics, site-directed mutagenesis (Cys127), nuclear fractionation, co-immunoprecipitation of FABP5-PPARβ/δ, Grx1 KO and conditional KO mice (Grx1fl/flLysMcre)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — PTM identified by redox proteomics, validated by site-specific mutagenesis, functional consequences confirmed in vivo with conditional KO\",\n      \"pmids\": [\"34876574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FABP5 regulates keratinocyte differentiation via 13(S)-HODE-mediated NF-κB activation. FABP5 facilitates incorporation of linoleic acid into cells; linoleic acid is then metabolized to 13(S)-HODE, which induces keratin 1 expression concomitant with increased NF-κB activity. E-FABP(-/-) keratinocytes show decreased 13(S)-HODE levels, reduced NF-κB activity, and decreased keratin 1 expression.\",\n      \"method\": \"E-FABP knockout mice, linoleic acid incorporation assays, 13(S)-HODE quantification, NF-κB reporter assays, keratinocyte differentiation markers\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined lipid metabolite (13(S)-HODE) as mechanistic intermediary and NF-κB as downstream effector, multiple orthogonal readouts\",\n      \"pmids\": [\"21068754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"E-FABP (FABP5) is highly expressed in macrophages and promotes antitumor activity by upregulating lipid droplet formation in response to tumors, leading to high IFN-β production. E-FABP-mediated IFN-β signaling enhances recruitment of NK cells to the tumor stroma.\",\n      \"method\": \"E-FABP KO mice, tumor-associated macrophage isolation, lipid droplet staining, IFN-β ELISA, NK cell recruitment assays, mammary tumor implantation model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular and molecular phenotype (IFN-β, lipid droplets, NK recruitment), single lab\",\n      \"pmids\": [\"24713431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FABP5 is a binding partner of HIF-1α, identified by proteomics. FABP5 enhances HIF-1α activity by promoting HIF-1α synthesis while disrupting FIH/HIF-1α interaction. Oleic acid treatment activates the FABP5/HIF-1α axis, promoting lipid accumulation and cell proliferation in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation proteomics to identify HIF-1α binding partners, FABP5 knockdown/overexpression, HIF-1α translation assay, FIH competitive binding assay, lipid accumulation measurement\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP-based partner identification with functional follow-up showing disruption of FIH/HIF-1α interaction, single lab with multiple methods\",\n      \"pmids\": [\"33128030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FABP5 acts as a central lipid chaperone linking cytosolic fatty acid metabolism (generated by FASN and MAGL) to pro-metastatic nuclear receptor signaling in prostate cancer. The pro-metastatic effects of FASN and MAGL are critically dependent on co-expression of FABP5 both in vitro and in vivo.\",\n      \"method\": \"ShRNA knockdown of FABP5, FASN, MAGL combinations; nuclear receptor activation assays; in vivo xenograft metastasis models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via combinatorial knockdown in vitro and in vivo, single lab\",\n      \"pmids\": [\"31831821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FABP5 promotes lipolysis of lipid droplets, de novo fatty acid synthesis, and NF-κB signaling in cancer cells. FABP5 knockdown downregulates HSL, MAGL, Elovl6, and ACSL1. FABP5 activates NF-κB through reactive oxygen species and protein kinase C.\",\n      \"method\": \"siRNA knockdown in prostate and breast cancer cells, gene expression analysis, ROS measurement, PKC activity assays, NF-κB reporter assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with defined molecular pathway components, single lab, multiple readouts\",\n      \"pmids\": [\"29906613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FABP5 selectively programs long-chain unsaturated fatty acid (particularly oleic acid) metabolism in macrophages. Fabp5 deletion causes accumulation of free long-chain unsaturated FAs; the mechanism involves enhanced FA β-oxidation, TCA cycle, and oxidative phosphorylation via activation of PPARγ signaling, reshaping macrophages toward M2 polarization.\",\n      \"method\": \"Myeloid-specific FABP5 conditional KO mice, OVA-induced allergic airway inflammation model, in vitro M2 polarization assays, lipidomics, metabolic flux analysis, PPARγ signaling readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with lipidomics and metabolic pathway analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36384126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FABP5 deletion in macrophages increases intracellular unsaturated fatty acids (especially oleic acid), which increases the AMP/ATP ratio and activates AMPK, thereby inhibiting the NF-κB pathway and reducing macrophage inflammatory responses. Pharmacological AMPK inhibition rescued the decreased NF-κB signaling in FABP5-KO macrophages.\",\n      \"method\": \"Myeloid-specific FABP5 KO mice, LPS-induced acute liver injury model, RNA-sequencing, AMP/ATP ratio measurement, AMPK activation assays, NF-κB pathway analysis, pharmacological rescue with AMPK inhibitor\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with RNA-seq pathway analysis and pharmacological rescue establishing AMPK-NF-κB axis, single lab\",\n      \"pmids\": [\"36426981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FABP5 directly binds to Raptor (the regulatory-associated protein of mTOR) to enhance formation of functional mTORC1 and substrate binding, activated by ω-6 linoleic acid. This constitutes a direct nutrient-sensing mechanism linking dietary linoleic acid to mTORC1 activation and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation of FABP5-Raptor, in vitro binding assays, mTORC1 activity assays, FABP5 KO cells, FABP5-linoleic acid binding assessment\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein-protein interaction (FABP5-Raptor) validated by Co-IP with functional mTORC1 reconstitution and loss-of-function, published in high-profile journal with multiple orthogonal methods\",\n      \"pmids\": [\"40080571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis in an FABP5-dependent manner. Mechanistically, FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Keratinocyte-specific (Krt6a-Cre) but not myeloid-specific (LysM-Cre) FABP5 deletion attenuates psoriatic symptoms.\",\n      \"method\": \"Global and conditional KO mice (Krt6a-Cre, LysM-Cre), proteomic analysis identifying FABP5-VCP interaction, Co-IP, siRNA silencing of FABP5 and VCP, NF-κB reporter assays, neutrophil chemotaxis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO epistasis combined with proteomic identification of binding partner (VCP), Co-IP validation, and signaling pathway analysis with multiple orthogonal methods\",\n      \"pmids\": [\"37967009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Long-chain unsaturated fatty acids (UFAs) released by tumor cells activate PPARγ via FABP5 in tumor-associated macrophages (TAMs), resulting in immunosuppressive properties. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression and enhances T cell-dependent antitumor immunity.\",\n      \"method\": \"Macrophage-specific FABP5 KO mice, single-cell RNA sequencing, in vitro UFA stimulation of macrophages, PPARγ signaling readouts, tumor growth assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with single-cell transcriptomics and PPARγ mechanistic validation, single lab\",\n      \"pmids\": [\"39357545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FABP5 overexpression in human fibroblasts causes nuclear translocation of SMAD2 and significant activation of the TGF-β signaling pathway, promoting profibrotic gene expression. Exogenous FABP5-EGFP can be incorporated by skin cells and intensify TGF-β signaling.\",\n      \"method\": \"FABP5 overexpression in WS1 fibroblasts, immunofluorescence of SMAD2 nuclear localization, TGF-β target gene expression, exogenous FABP5-EGFP uptake\",\n      \"journal\": \"Radiation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with defined signaling readout (SMAD2 nuclear translocation) and exogenous protein uptake demonstrated, single lab\",\n      \"pmids\": [\"29215326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FABP5 overexpression in prostate cancer is caused by hypomethylation of a CpG island in its promoter region, coupled with upregulation of direct trans-acting transcription factors Sp1 and c-Myc. Silencing Sp1, c-Myc, or FABP5 significantly decreases cancer cell proliferation.\",\n      \"method\": \"Bisulfite sequencing, COBRA, qAMP methylation analysis; Sp1 and c-Myc siRNA knockdown; proliferation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epigenetic mechanism defined by bisulfite sequencing with functional validation via transcription factor knockdown, single lab\",\n      \"pmids\": [\"26614767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E-FABP (FABP5) induces differentiation markers (K10, involucrin) in normal human keratinocytes. E-FABP inhibition by siRNA downregulates K10 and involucrin through NF-κB and JNK signaling pathways.\",\n      \"method\": \"Recombinant E-FABP transfection, siRNA knockdown, differentiation marker expression (K10, involucrin), NF-κB and JNK pathway assays\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — bidirectional (gain and loss of function) with defined pathway readouts (NF-κB, JNK), single lab\",\n      \"pmids\": [\"23528210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E-FABP binds a broad range of saturated and unsaturated long-chain fatty acids including DHA, EPA, and arachidonic acid. E-FABP expression is required for normal neurite extension in NGF-differentiated PC12 cells; antisense knockdown reduces neurite number/length, and replenishment with recombinant E-FABP restores neurite outgrowth. E-FABP localizes to cytoplasm and nuclear regions of neurons.\",\n      \"method\": \"FABP radiobinding analysis, antisense PC12 clones, recombinant E-FABP protein rescue, neurite measurement, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — antisense knockdown plus recombinant protein rescue with defined cellular phenotype, single lab\",\n      \"pmids\": [\"18513372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FABP5 promotes intracellular transport and inactivation of endocannabinoids (including anandamide) in intestinal K cells. FABP5-deficient mice have significantly decreased circulating GIP levels in the fasting state and in response to acute oral fat diet administration, establishing FABP5 as a regulator of GIP secretion via endocannabinoid control.\",\n      \"method\": \"FABP5-KO mice, GIP-GFP reporter knock-in mice, RNA-seq of purified K cells, GIP ELISA from plasma after fat challenge\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined hormonal phenotype (GIP) and mechanistic link (endocannabinoid transport), single lab\",\n      \"pmids\": [\"25268051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FABP5 deletion specifically in TRPV1+ nociceptors augments anandamide levels, producing antinociceptive effects mediated by CB1. Mechanistically, FABP5 deletion suppresses inflammation- and NGF-mediated TRPV1 sensitization via CB1 through calcineurin. FABP5 functions as an intracellular AEA carrier to FAAH for inactivation in nociceptors.\",\n      \"method\": \"Conditional FABP5 KO (TRPV1-Cre), anandamide quantification, TRPV1 sensitization assays (capsaicin, NGF), CB1 antagonist pharmacology, calcineurin inhibitor studies, FAAH inhibitor comparison\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with pharmacological dissection of CB1/calcineurin mechanism and comparison with FAAH inhibition, multiple orthogonal readouts\",\n      \"pmids\": [\"35655086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"E-FABP (FABP5) and S100A7 form a complex in the cytosol of human keratinocytes. Gel filtration and non-denaturing PAGE showed S100A7 co-purifies with E-FABP; co-immunoprecipitation confirmed their association in protein extracts from psoriatic scales.\",\n      \"method\": \"Gel filtration chromatography, non-denaturing PAGE, co-immunoprecipitation from psoriatic keratinocyte extracts\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-purification and co-IP with two orthogonal native methods, single lab\",\n      \"pmids\": [\"10331666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FABP5 knockdown in RPE cells decreases cholesterol and cholesterol ester levels by ~40%, increases triglycerides by 67%, and decreases apoB100 secretion by 76%, demonstrating that FABP5 plays a critical role in lipid metabolism and lipoprotein particle formation in retinal pigment epithelial cells.\",\n      \"method\": \"siRNA knockdown in ARPE-19 cells, lipid class quantification, apoB100 ELISA, lipoprotein secretion assay\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA knockdown with multiple quantitative lipid and lipoprotein readouts, single lab\",\n      \"pmids\": [\"19434059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Both FABP7 and FABP5 are required for normal proliferation and differentiation of neural stem/progenitor cells in the postnatal hippocampal dentate gyrus. FABP5 KO reduces the number of mature oligodendrocytes with membrane sheet morphology, and FABP7/FABP5 double KO dramatically reduces NSC/NPC numbers while increasing survival of BrdU+ cells and enhancing neuronal differentiation.\",\n      \"method\": \"Single and double FABP KO mice, BrdU incorporation and survival tracking, immunofluorescent staging of NSC/NPC differentiation markers\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cell-type-specific phenotypic readouts and epistasis between FABP7 and FABP5, single lab\",\n      \"pmids\": [\"22581784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"E-FABP KO mice show impaired recovery of transepidermal water loss (TEWL) after skin lipid barrier disruption by acetone, with lower basal TEWL. H-FABP expression is specifically elevated in liver of neonatal heterozygous and homozygous mice, suggesting functional compensation by H-FABP for E-FABP deficiency.\",\n      \"method\": \"E-FABP KO mice, TEWL measurement after acetone treatment, Northern blot for compensatory FABP expression\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined functional phenotype (TEWL) and compensatory mechanism (H-FABP upregulation), single lab\",\n      \"pmids\": [\"12479572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FABP5 co-localizes with α-synuclein (αSyn) in mitochondria under oxidative stress (rotenone treatment), reducing mitochondrial membrane potential and promoting cell death. Pharmacological inhibition of FABP5 prevented αSyn accumulation in mitochondria and rescued cell viability.\",\n      \"method\": \"Co-overexpression of FABP5 and αSyn in Neuro-2A cells, rotenone treatment, co-localization immunofluorescence, mitochondrial membrane potential assay, FABP5 pharmacological inhibitor rescue\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization with mitochondrial functional readout and pharmacological rescue, single lab\",\n      \"pmids\": [\"33499263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Palmitate acid promotes nuclear transport of FABP5, which then increases nuclear SP1 protein levels, consequently increasing UCA1 expression in gastric cancer cells and promoting metastatic properties.\",\n      \"method\": \"Immunofluorescence of FABP5 nuclear translocation after PA treatment, siRNA knockdown of FABP5 and SP1, Western blot, RT-PCR for UCA1, migration/invasion assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ligand-induced nuclear translocation with downstream transcription factor (SP1) and target (UCA1) validated by siRNA, single lab\",\n      \"pmids\": [\"30948929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FABP5 modulates PPARγ activity in airway epithelial cells; FABP5 overexpression increases expression of β-defensin-2 and limits IL-8 production against Pseudomonas aeruginosa infection. FABP5 knockdown increases bacterial load and inflammatory cytokine production. FABP5 exerts protective immunomodulatory functions through modulation of PPARγ activity.\",\n      \"method\": \"FABP5 knockdown and overexpression in primary NHBE cells, P. aeruginosa infection assay, β-defensin-2 and IL-8 quantification, PPARγ activity assay, cigarette smoke exposure\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — bidirectional expression manipulation with defined antimicrobial and inflammatory readouts and PPARγ pathway link, single lab\",\n      \"pmids\": [\"23349676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FABP5 deficiency in cardiac fibroblasts increases oxidative stress, reduces mitochondrial respiration, and increases myofibroblast activation markers in response to TGF-β. In FABP5 KO mice with TAC-induced cardiac remodeling, FABP5 deficiency aggravates cardiac hypertrophy, fibrosis, and mitochondrial impairment.\",\n      \"method\": \"FABP5 global KO mice with TAC surgery, echocardiography, transmission electron microscopy, ATP detection, siRNA in primary cardiac fibroblasts, mitochondrial respiration assay, oxidative stress assay\",\n      \"journal\": \"Cardiovascular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model combined with in vitro siRNA mechanistic analysis of mitochondrial function, single lab\",\n      \"pmids\": [\"33929718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FABP5 knockdown in 3T3-L1 preadipocytes during adipocytic induction triggers apoptosis via caspase-3 activation and reduces expression of PPARγ and C/EBPα. FABP5 is required for preadipocyte viability during adipogenesis through activation of the Akt cascade.\",\n      \"method\": \"siRNA knockdown in 3T3-L1 cells during adipogenic induction, caspase-3 activity assay, procaspase-3 cleavage, PPARγ/C/EBPα Western blot, Akt phosphorylation assay\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA knockdown with defined apoptotic and signaling readouts, single lab\",\n      \"pmids\": [\"20238174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MELK kinase binds to FABP5 and stabilizes it by affecting its ubiquitination through the K48R pathway, thereby activating the Akt/mTOR signaling axis in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation of MELK-FABP5, ubiquitination assay identifying K48-linked ubiquitin chain modification, Akt/mTOR pathway readouts, MELK knockdown\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with ubiquitination type characterized and downstream signaling validated, single lab\",\n      \"pmids\": [\"39871325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM45 E3 ligase directly adds K33-type and K63-type poly-ubiquitin chains to the NLS domain of FABP5, promoting FABP5 nuclear translocation. Nuclear FABP5 then interacts with PPARγ to facilitate downstream lipid synthesis gene expression.\",\n      \"method\": \"IP-tandem mass spectrometry identifying TRIM45-FABP5 interaction, ubiquitin linkage-specific assay (K33/K63), nuclear fractionation, FABP5-PPARγ Co-IP, gene expression of lipid synthesis targets\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified ubiquitination with linkage specificity, nuclear translocation validated, PPARγ interaction confirmed by Co-IP, single lab\",\n      \"pmids\": [\"38755308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Asprosin interacts with FABP5, and this interaction facilitates abnormal nuclear localization of asprosin. Nuclear asprosin directly binds to and inhibits PPARα transcriptional activity at PPRE elements, disrupting hepatic fatty acid β-oxidation. GalNAc-siRNA targeting hepatic FABP5 ameliorates hepatic steatosis in MASLD.\",\n      \"method\": \"Co-IP of asprosin-FABP5, nuclear fractionation, PPRE reporter assay, ChIP for asprosin at PPREs, hepatocyte-specific asprosin overexpression/knockdown, GalNAc-siRNA targeting FABP5\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with nuclear localization mechanism validated by ChIP and reporter assay, in vivo GalNAc-siRNA intervention, single lab\",\n      \"pmids\": [\"40231957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FABP5 interacts with fatty acid synthase (FASN) and promotes FASN degradation through the ubiquitin proteasome pathway, leading to decreased FASN expression, reduced lipid accumulation, and suppression of mTOR signaling to facilitate autophagy in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of FABP5-FASN, ubiquitin proteasome pathway assay, mTOR signaling readouts, autophagy assays, FABP5 KO/overexpression in CRC cells\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with proteasome pathway validation and defined signaling outcome, single lab\",\n      \"pmids\": [\"37416772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FABP5 interacts with FASN in pancreatic neuroendocrine neoplasm cells and regulates FASN expression via the ubiquitin proteasome pathway. FABP5 promotes lipid droplet deposition and activates the WNT/β-catenin signaling pathway to facilitate pNEN progression.\",\n      \"method\": \"Co-immunoprecipitation of FABP5-FASN, ubiquitin proteasome pathway assay, lipid droplet staining, WNT/β-catenin reporter assays, FABP5 knockdown/overexpression\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with proteasome validation and WNT/β-catenin pathway link, single lab\",\n      \"pmids\": [\"37302809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FABP5 in macrophage monocytes activates FABP5 expression and decreases β-oxidation, causing lipid droplet accumulation. This FABP5-mediated lipid accumulation increases IL-10 secretion by suppressing the PPARα pathway. The elevated IL-10 then promotes PD-L1 expression on Treg cells via JNK-STAT3 pathway activation, fostering immune tolerance in HCC.\",\n      \"method\": \"FABP5 knockdown in monocytes, β-oxidation assay, lipid droplet staining, IL-10 ELISA, PPARα pathway analysis, PD-L1 expression on Tregs, JNK-STAT3 signaling\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — individual pathway components shown but mechanistic chain from FABP5-lipid accumulation to PPARα to IL-10 to JNK-STAT3-PD-L1 relies on multiple inferential steps, single lab\",\n      \"pmids\": [\"35902729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"E-FABP (FABP5) expressed in T cells facilitates linoleic acid (LA) mitochondrial transport and cardiolipin incorporation. LA induces mitochondrial ROS production and lipid peroxidation in T cells; E-FABP genetic depletion rescues LA-impaired T-cell responses and suppresses LA-rich HFD-associated mammary tumor growth.\",\n      \"method\": \"E-FABP KO mice on high-fat diet, LA/OA fatty acid uptake comparison, mitochondrial ROS measurement, cardiolipin incorporation assay, T cell apoptosis and TNFα production assays, tumor growth\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined lipid transport mechanism (cardiolipin incorporation) and mitochondrial ROS readout, single lab with in vivo confirmation\",\n      \"pmids\": [\"34400394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR171 deficiency promotes Th17 cell differentiation and alters lipidome via the cAMP-pCREB-FABP5 axis. Blockade of FABP5 reduces Th17 cell differentiation in vitro and ameliorates DSS-induced colitis in Gpr171-/- mice, placing FABP5 downstream of GPR171/cAMP/pCREB in Th17 differentiation.\",\n      \"method\": \"GPR171 KO mice, BigLEN ligand treatment, cAMP/pCREB pathway analysis, FABP5 inhibitor treatment, RNA-seq, lipidomics, DSS colitis model with Gpr171-/- background\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (GPR171 KO rescued by FABP5 inhibitor) with defined signaling axis, single lab\",\n      \"pmids\": [\"40074327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lysine enhances fatty acid-stimulated milk fat synthesis through GPRC6A-PI3K-FABP5 signaling in bovine mammary epithelial cells. Lysine stimulates FABP5 expression via GPRC6A-PI3K signaling, and FABP5 in turn enhances SREBP-1c expression and maturation to drive milk fat synthesis.\",\n      \"method\": \"siRNA knockdown of FABP5 and GPRC6A, PI3K inhibitor treatment, SREBP-1c maturation assay, lipid droplet/milk fat quantification in BMECs\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA epistasis at multiple pathway nodes with functional metabolic readout, single lab\",\n      \"pmids\": [\"31174423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The FABP5 inhibitor ART26.12 selectively binds FABP5 compared to FABP3, FABP4, and FABP7, and produces CB1-dependent anti-allodynic effects in an oxaliplatin-induced peripheral neuropathy model; spinal cord lipidomics revealed widespread lipid modulation including N-acyl amino acids.\",\n      \"method\": \"Binding selectivity (MST/fluorescence), CB1 antagonist pharmacology, OIPN mouse model with acute and repeated dosing, multi-scale lipidomics of spinal cord\",\n      \"journal\": \"The journal of pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological selectivity profiling plus CB1 pharmacological epistasis in in vivo pain model with lipidomics, single lab\",\n      \"pmids\": [\"38232863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fatty acid binding properties of FABP5 characterized by EPR spectroscopy: FABP5 shows two distinct binding states ('intermediately' and 'strongly' bound) for fatty acid ligands; the proportion and dynamics of binding depend on FABP concentration and temperature, with the more dynamic 'intermediately bound' state dominating at body temperature.\",\n      \"method\": \"CW-EPR spectroscopy with spin-labeled fatty acids (5/16-DOXYL stearic acid), microscale thermophoresis, dynamic light scattering, EPR spectral simulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biophysical characterization of ligand binding states using EPR, single lab, no mutagenesis or functional validation\",\n      \"pmids\": [\"38777142\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FABP5 is an intracellular lipid chaperone that binds long-chain (particularly polyunsaturated) fatty acids and endocannabinoids within a β-barrel structure; specific polyunsaturated fatty acids allosterically expose a nuclear localization signal in the α-helical cap, driving cytoplasm-to-nucleus translocation where FABP5 delivers ligands to activate PPARβ/δ or PPARγ and regulate gene transcription. FABP5 also transports anandamide to FAAH for inactivation (modulating endocannabinoid and CB1 signaling), directly binds Raptor to activate mTORC1 in response to ω-6 linoleic acid, interacts with binding partners including VCP (activating NF-κB), HIF-1α (promoting its synthesis), FASN (regulating its ubiquitin-proteasome degradation), and asprosin (enabling its nuclear localization to inhibit PPARα). Post-translational regulation includes S-glutathionylation at Cys127 (promoting nuclear translocation and PPARβ/δ interaction), K33/K63-ubiquitination by TRIM45 at the NLS domain (promoting nuclear translocation), and K48-linked ubiquitin stabilization by MELK. In immune cells, FABP5 governs fatty acid oxidation, macrophage polarization, and T cell function, while in keratinocytes it promotes differentiation and NF-κB-mediated neutrophil recruitment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FABP5 (epidermal fatty acid-binding protein) is an intracellular lipid chaperone that binds long-chain saturated and unsaturated fatty acids — including arachidonic, linoleic, and docosahexaenoic acids — within a β-barrel of ten anti-parallel β-strands, coupling cytosolic lipid metabolism to nuclear and signaling outputs [#1, #18, #40]. Its central regulatory feature is ligand-gated nuclear import: 'activating' cis-bonded polyunsaturated fatty acids permit allosteric communication between the β2 ligand-sensing loop and a tertiary nuclear localization signal in the α-helical cap, driving cytoplasm-to-nucleus translocation, whereas saturated fatty acids destabilize this activation loop [#0]. Once nuclear, FABP5 delivers fatty acid ligands to PPARβ/δ and PPARγ to potentiate their transcriptional activity, a function essential for HER2-driven mammary tumorigenesis and for shuttling arachidonic acid to PPARβ/δ in brain to support hippocampal learning [#2, #3, #14]. FABP5 simultaneously governs endocannabinoid disposition by carrying anandamide to FAAH for hydrolysis, modulating CB1 signaling in nociceptors and controlling GIP secretion in intestinal K cells [#3, #19, #20]. Beyond nuclear receptors, FABP5 directly binds Raptor to assemble functional mTORC1 in response to ω-6 linoleic acid, and engages additional partners — VCP to drive NF-κB-dependent neutrophil recruitment, HIF-1α to enhance its synthesis, FASN to direct its proteasomal degradation, and asprosin to enable nuclear inhibition of PPARα [#12, #13, #7, #33, #32]. In immune cells FABP5 programs long-chain unsaturated fatty acid metabolism, fatty acid β-oxidation, and macrophage M2/immunosuppressive polarization, and shapes T cell and Th17 responses [#10, #14, #36, #37]; in keratinocytes it promotes differentiation through 13(S)-HODE-driven NF-κB signaling [#5, #17]. Its activity is tuned post-translationally by S-glutathionylation at Cys127 and by ubiquitination of the NLS domain by TRIM45 (K33/K63) or stabilization via MELK (K48), all of which favor nuclear translocation and PPAR engagement [#4, #31, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing the three-dimensional fold and dynamics of FABP5 was the prerequisite for understanding how it sequesters and releases lipid ligands.\",\n      \"evidence\": \"Multidimensional NMR structure determination with 15N relaxation and H/D exchange of human E-FABP\",\n      \"pmids\": [\"12049637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define ligand-bound conformational changes\", \"No link between dynamics and nuclear translocation yet\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining FABP5's ligand spectrum and a cellular requirement showed it is a broad long-chain fatty acid carrier with functional consequences in neurons.\",\n      \"evidence\": \"Radiobinding analysis plus antisense knockdown and recombinant protein rescue in NGF-differentiated PC12 cells\",\n      \"pmids\": [\"18513372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve molecular downstream effector for neurite outgrowth\", \"Nuclear vs cytoplasmic roles not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic epistasis established FABP5 as the lipid-delivery arm of PPARβ/δ transcriptional signaling driving proliferation.\",\n      \"evidence\": \"FABP5-null × MMTV-ErbB2 mouse cross plus ectopic expression with PPARδ target gene readouts\",\n      \"pmids\": [\"23722546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the operative endogenous ligand not pinned down\", \"Mechanism of nuclear import not yet structural\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A crystal structure resolved how specific polyunsaturated fatty acids allosterically expose the NLS, providing the atomic basis for ligand-selective nuclear translocation.\",\n      \"evidence\": \"X-ray crystallography, HDX-MS, fluorescence anisotropy and translocation assays comparing linoleic/arachidonic vs saturated fatty acids\",\n      \"pmids\": [\"24692551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the nuclear receptor handoff structurally\", \"Cellular ligand-sensing kinetics not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Knockout studies revealed a dual role in endocannabinoid biology — FABP5 both promotes anandamide hydrolysis and delivers arachidonic acid to nuclear PPARβ/δ — linking it to learning and hormone secretion.\",\n      \"evidence\": \"FABP5-KO mice with AEA quantification, PPARβ/δ target genes, behavioral testing, and GIP reporter knock-in mice\",\n      \"pmids\": [\"24644281\", \"25268051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative flux to FAAH vs nucleus in vivo unquantified\", \"Tissue-specific partitioning of the two functions unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a lipid-metabolite pathway whereby FABP5 channels linoleic acid to 13(S)-HODE to activate NF-κB and drive keratinocyte differentiation.\",\n      \"evidence\": \"E-FABP KO keratinocytes with linoleic acid incorporation, 13(S)-HODE quantification, NF-κB reporters and differentiation markers\",\n      \"pmids\": [\"21068754\", \"23528210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FABP5 enhances LA incorporation unresolved\", \"Direct vs indirect role in NF-κB activation not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying S-glutathionylation at Cys127 showed redox state directly gates FABP5 nuclear translocation and PPARβ/δ engagement, tying oxidative signaling to its activity.\",\n      \"evidence\": \"Redox proteomics, Cys127 mutagenesis, nuclear fractionation, FABP5-PPARβ/δ Co-IP, Grx1 conditional KO mice\",\n      \"pmids\": [\"34876574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural effect of Cys127 modification on NLS not solved\", \"Crosstalk with ligand-induced translocation unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Conditional and tissue-specific knockouts established FABP5 as a programmer of immune cell lipid metabolism, controlling macrophage polarization and inflammatory tone through PPARγ, AMPK and NF-κB.\",\n      \"evidence\": \"Myeloid- and keratinocyte-specific KO mice with lipidomics, metabolic flux, AMPK/NF-κB analysis, and VCP partner identification in psoriasis models\",\n      \"pmids\": [\"36384126\", \"36426981\", \"37967009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PPARγ, AMPK and VCP routes operate in parallel or sequentially unresolved\", \"Direct ligand sensed in each immune context not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery of NLS-domain ubiquitination by TRIM45 and K48 stabilization by MELK added a ubiquitin-code layer controlling FABP5 nuclear translocation and stability.\",\n      \"evidence\": \"IP-MS, linkage-specific ubiquitination assays (K33/K63 and K48R), nuclear fractionation, FABP5-PPARγ Co-IP and Akt/mTOR readouts\",\n      \"pmids\": [\"38755308\", \"39871325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between ubiquitination and glutathionylation not tested\", \"Deubiquitinases not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Direct binding to Raptor revealed a nuclear-receptor-independent function — FABP5 acts as a linoleic acid sensor that assembles functional mTORC1.\",\n      \"evidence\": \"Co-IP of FABP5-Raptor, in vitro binding, mTORC1 activity assays in FABP5-KO cells with linoleic acid\",\n      \"pmids\": [\"40080571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the FABP5-Raptor interface unknown\", \"Whether ligand binding modulates Raptor engagement unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"FABP5 was shown to carry asprosin into the nucleus to inhibit PPARα, extending its chaperone role to a protein cargo with metabolic-disease consequences.\",\n      \"evidence\": \"Asprosin-FABP5 Co-IP, nuclear fractionation, PPRE ChIP/reporter assays, and hepatic GalNAc-siRNA in a MASLD model\",\n      \"pmids\": [\"40231957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether asprosin uses the lipid-gated NLS mechanism unknown\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple competing inputs — ligand identity, Cys127 redox state, TRIM45/MELK ubiquitination, and protein partners (Raptor, VCP, HIF-1α, FASN, asprosin) — are integrated to determine FABP5 localization and which output pathway is engaged in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling cytoplasmic Raptor binding vs nuclear PPAR delivery\", \"Quantitative hierarchy of PTMs and partners untested\", \"Structural basis for most protein-protein interactions absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 18, 40]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3, 19, 20, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 12, 32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 31, 26]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [25, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 31]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 10, 22, 36]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 10, 14, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [30, 31, 33]}\n    ],\n    \"complexes\": [\"mTORC1\"],\n    \"partners\": [\"PPARD\", \"PPARG\", \"RPTOR\", \"VCP\", \"HIF1A\", \"FASN\", \"S100A7\", \"TRIM45\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}