{"gene":"ACOX1","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":2018,"finding":"SIRT5-mediated desuccinylation inhibits ACOX1 enzymatic activity by suppressing its active dimer formation. SIRT5 is present in peroxisomes and ACOX1 is a physiological substrate of SIRT5; deletion of SIRT5 increases ACOX1 succinylation and activity, leading to elevated H2O2 production and oxidative DNA damage that is rescued by ACOX1 knockdown.","method":"Co-IP, deacylase activity assay, SIRT5 knockout mouse livers, ACOX1 knockdown rescue experiments, succinylation proteomics","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical interaction, genetic rescue (SIRT5 KO + ACOX1 KD), multiple orthogonal methods in cultured cells and mouse livers","pmids":["29491006"],"is_preprint":false},{"year":2020,"finding":"Loss-of-function mutations in ACOX1 cause glial and axonal loss via accumulation of very-long-chain fatty acids and peroxisomal dysfunction, whereas a gain-of-function variant (p.N237S) causes increased ACOX1 protein levels and elevated reactive oxygen species in glia (Schwann cells/oligodendrocytes), leading to neurodegeneration via a distinct oxidative-stress mechanism. Antioxidant treatment suppressed p.N237S-induced neurodegeneration in flies and primary Schwann cells.","method":"Drosophila ACOX1 loss-of-function genetics, patient-derived murine Schwann cells expressing N237S variant, ROS assays, antioxidant rescue experiments","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple model systems (Drosophila genetics, mammalian primary cells, patient samples), mechanistic rescue experiments, two distinct mutational mechanisms established","pmids":["32169171"],"is_preprint":false},{"year":2023,"finding":"DUSP14 phosphatase dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation. Loss of ACOX1 leads to accumulation of its substrate palmitic acid (PA), which palmitoylates β-catenin at cysteine 466, blocking CK1/GSK3-directed phosphorylation and β-TrCP-mediated degradation of β-catenin, thereby stabilizing β-catenin and activating Wnt signaling to promote colorectal cancer progression. Stabilized β-catenin in turn transcriptionally represses ACOX1 and activates DUSP14 via c-Myc, forming a feedforward loop.","method":"In vitro dephosphorylation assay, co-IP, ubiquitination assay, site-directed mutagenesis (S26), palmitoylation assay, mouse xenograft models, patient-derived xenograft experiments, CRC clinical samples","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods (in vitro assay, mutagenesis, co-IP, palmitoylation assay), in vivo models, and clinical validation in one study","pmids":["36878899"],"is_preprint":false},{"year":2010,"finding":"Human ACOX1 has two isoforms (ACOX1a and ACOX1b) from a single gene; ACOX1b is markedly more effective than ACOX1a in reversing the Acox1-null hepatic phenotype in mice. ACOX1b expression restores nervonic acid production, which negatively impacts recruitment of coactivators to the PPARα-response unit (suggesting nervonic acid/nervonoyl-CoA as endogenous PPARα antagonist). Restoration of DHA requires concomitant expression of both isoforms.","method":"Adenoviral ACOX1a/b expression in Acox1-/- mice, fatty acid profiling, PPARα coactivator recruitment assay, liver phenotype analysis","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic rescue experiment with two isoforms, fatty acid profiling, and transcriptional coactivator recruitment assay in Acox1 knockout mice","pmids":["20195242"],"is_preprint":false},{"year":2024,"finding":"Hepatic ACOX1-mediated peroxisomal β-oxidation catabolizes very-long-chain fatty acids (VLCFA, C24–C28 ω-3 species); liver-specific Acox1 knockout increases circulating ω-3 VLCFAs that promote adipose browning, mitochondrial biogenesis, and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes, establishing an inter-organ communication axis regulating metabolic homeostasis.","method":"Liver-specific Acox1 knockout mice, serum lipidomics, white adipocyte browning assay, GPR120 signaling assay, conditioned serum experiments on cultured adipocytes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — liver-specific KO with lipidomics, mechanistic receptor identification (GPR120), multiple orthogonal functional readouts in vitro and in vivo","pmids":["38760332"],"is_preprint":false},{"year":2020,"finding":"ACOX1 is the key peroxisomal fatty acid β-oxidation enzyme supporting metabolic reprogramming from glycolysis to oxidative respiration in BRAF(V600E) melanoma persister cells tolerant to BRAF/MEK inhibitors. Knockdown of ACOX1 or treatment with the peroxisomal FAO inhibitor thioridazine specifically suppresses oxidative respiration of persister cells and decreases their emergence. PPARα transcriptionally regulates this FAO program.","method":"ACOX1 siRNA knockdown, thioridazine pharmacological inhibition, Seahorse metabolic flux assay, mouse xenograft experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KD and pharmacological inhibition with orthogonal metabolic readouts, in vivo mouse model confirmation","pmids":["33238129"],"is_preprint":false},{"year":2024,"finding":"O-GlcNAcylation by OGT (O-GlcNAc transferase) protects ACOX1 from ubiquitination-dependent proteasomal degradation. The OGT-ACOX1 interaction at the K48 site precludes K48-linked ubiquitination; deletion of O-GlcNAcylation disrupts lipid metabolism with accumulation of medium- and long-chain fatty acids.","method":"Co-immunoprecipitation, ubiquitination assay, OGT knockout mice, in vitro lipid metabolism analysis, AML-12 cell OGT inhibitor treatment","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP interaction and ubiquitination assay shown, single lab, mechanistic follow-up in cells and mice","pmids":["38547945"],"is_preprint":false},{"year":2019,"finding":"ACOX1 processes prostaglandin E2 (PGE2) as a substrate; the miR-31-5p–ACOX1 axis controls extracellular PGE2 levels in OSCC cells, modulating cell migration and invasion through EP1–ERK–MMP9 signaling. miR-31-5p directly suppresses ACOX1 expression, leading to PGE2 accumulation and enhanced cell motility.","method":"miR-31-5p overexpression/knockdown, ACOX1 knockdown, lipidomics, PGE2 ELISA, migration/invasion assays, EP1/ERK/MMP9 pathway analysis","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct manipulation of ACOX1 and miR-31-5p with lipidomic substrate profiling and downstream signaling, single lab","pmids":["29290822"],"is_preprint":false},{"year":2019,"finding":"ACOX1 overexpression in lymphoma cells destabilizes p73 protein (but not p53), reducing p73 expression. Downregulation of ACOX1 promotes mitochondrial translocation of Bad, reduces mitochondrial membrane potential, and activates caspase-9 and caspase-3-dependent apoptosis. p73 expression is required for the apoptotic induction seen upon ACOX1 knockdown.","method":"ACOX1 overexpression/knockdown, caspase activity assay, mitochondrial membrane potential assay, mitochondrial fractionation (Bad localization), p73 stability assay","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple cell biology assays establishing pathway, single lab, single cancer type","pmids":["31401980"],"is_preprint":false},{"year":2020,"finding":"EV71 non-structural protein 3D (RdRp) directly interacts with ACOX1 protein and promotes ACOX1 downregulation. ACOX1 knockdown alone induces apoptosis and autophagy in neural cells, reduces peroxisome numbers, increases ROS, and attenuates the DJ-1/NRF2/HO-1 cytoprotective pathway.","method":"Co-IP (3D–ACOX1 interaction), ACOX1 siRNA knockdown, peroxisome counting, ROS assay, apoptosis/autophagy assays, NRF2/HO-1 pathway analysis","journal":"Virulence","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct co-IP for viral protein–ACOX1 interaction, genetic KD with multiple functional readouts, single lab","pmids":["32434419"],"is_preprint":false},{"year":2021,"finding":"In Haemonchus contortus (parasitic nematode), ACOX1 proteins show fatty acid oxidation activity in vitro and in vivo and interact with the peroxisomal targeting receptor PEX-5 via a peroxisomal targeting signal type 1 (PTS1) sequence. PTS1 is required for ACOX-1 recognition by PEX-5. Knockdown of acox-1 impairs post-embryonic larval development.","method":"In vitro and in vivo fatty acid oxidation assay, co-IP (ACOX-1/PEX-5), PTS1 mutagenesis, RNAi knockdown, developmental phenotyping","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution of enzymatic activity, co-IP with PTS1 mutagenesis validation, single organism/lab (nematode ortholog)","pmids":["34270617"],"is_preprint":false},{"year":2022,"finding":"PPARα transcriptionally regulates ACOX1 mRNA and protein expression (but not catalase). PPARα agonist WY-14,643 induces ACOX1 to a greater extent than catalase; after agonist withdrawal, ACOX1 returns to baseline faster. In liver-specific PEX16 knockout (peroxisome-absent) mice crossed with Pparα-/- mice, upregulated ACOX1 protein is suppressed by PPARα ablation, while catalase remains elevated.","method":"PPARα agonist/withdrawal experiments, liver-specific PEX16 KO and Pparα-/- double-KO mice, mRNA and protein quantification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout (double KO model) with mRNA and protein evidence, single lab","pmids":["40580723"],"is_preprint":false},{"year":2022,"finding":"PPARα agonist WY-14,643 induces a PLA2/COX-2/ACOX1 pathway in which arachidonic acid (AA) released by PLA2 from phospholipids is metabolized by ACOX1 (oxidizing PGE2). ACOX1-specific inhibitor restores both WY-14,643-suppressed liver TG and PGE2 levels, establishing that ACOX1 oxidizes PGE2/AA as substrates downstream of the PLA2/COX-2 axis in peroxisomal FAO.","method":"PPARα agonist treatment in mice (liquid diet), ACOX1-specific inhibitor (10,12-tricosadiynoic acid), COX-2 inhibitor, liver TG and PGE2 measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological pathway dissection with specific inhibitors and metabolite quantification, single lab","pmids":["35526488"],"is_preprint":false},{"year":2023,"finding":"ACOX1 downregulation in renal allografts is induced by TLR4–NF-κB signaling via DNA methyltransferase 1 (DNMT1)-dependent promoter methylation. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), promoting epithelial-mesenchymal transition (EMT) and extracellular matrix reorganization via endoplasmic reticulum (ER) stress, causing fibrosis.","method":"TLR4/NF-κB pathway manipulation, DNMT1 inhibition, ACOX1 KD/KO in renal cells, ER stress assay, EMT/ECM markers, rat renal transplant model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple pathway interventions in vitro and in vivo rat model, single lab","pmids":["38367917"],"is_preprint":false},{"year":2025,"finding":"MOXD1 directly interacts with the ACOX1–PEX5 translocation complex, promoting ACOX1 trafficking to peroxisomes and blocking lipolysis/lipophagy. Four key MOXD1 residues required for ACOX1 binding were identified. A small molecule (rM15) that directly binds MOXD1 and blocks its interaction with ACOX1 reduces hepatocyte lipid accumulation and suppresses diet-induced MASH in vivo.","method":"Co-IP mass spectrometry, structural modelling, colocalization analysis, hepatocyte-specific transgenic/KO mice, AAV8 knockdown model, small molecule screening and in vitro/in vivo pharmacology","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP-MS identifying interaction, structural modelling identifying interface residues, multiple genetic models, in vivo pharmacological validation","pmids":["42167911"],"is_preprint":false},{"year":2025,"finding":"CLIC1 protein binds ACOX1 protein, reduces ACOX1 stability, and facilitates its polyubiquitination-dependent proteasomal degradation, thereby decreasing ACOX1 levels and enhancing cellular oxidative stress to promote gastric cancer progression.","method":"Co-IP (CLIC1–ACOX1), ubiquitination assay, ACOX1 knockdown/overexpression, oxidative stress assay, gastric cancer cell proliferation/migration assays","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction with ubiquitination assay, single lab, functional phenotype established","pmids":["41093222"],"is_preprint":false},{"year":2025,"finding":"Glucose starvation induces crotonylation of DDX1 (DEAD-box helicase 1) at lysine 490 (regulated by crotonyltransferase GCN5 and decrotonylase HDAC1), enhancing DDX1 interaction with HNRNPK, which mediates mutually exclusive alternative splicing of ACOX1. The resulting ACOX1 splice variant promotes peroxisomal ROS generation, enhancing oxidative damage and suppressing colorectal cancer cell proliferation.","method":"Crotonylation site mapping, DDX1 K490 mutagenesis, HNRNPK co-IP, ACOX1 alternative splicing analysis (RT-PCR/RNA-seq), ROS assay, CRC cell proliferation assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — PTM site mapping with mutagenesis, co-IP, splicing analysis, functional ROS/proliferation readouts, single lab","pmids":["41197750"],"is_preprint":false},{"year":2025,"finding":"Hypoxia induces HIF-1α-dependent transcriptional upregulation of ACOX1, which increases crotonyl-CoA levels driving site-specific crotonylation of HSP90AB1 at lysine 265. K265 crotonylation induces conformational compaction of HSP90AB1, strengthening its interaction with thioredoxin (TXN) and enhancing TXN stability to buffer ROS. Pharmacological inhibition of ACOX1 (10,12-tricosadiynoic acid) or K265R mutagenesis disrupts this axis and synergizes with cisplatin to suppress tumor growth.","method":"HIF-1α manipulation, ACOX1 inhibitor treatment, HSP90AB1 K265 mutagenesis, crotonylation proteomics, molecular dynamics simulation, co-IP (HSP90AB1–TXN), in vivo tumor xenograft","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM site mutagenesis, molecular dynamics, co-IP, pharmacological inhibition with in vivo validation, single lab","pmids":["41675575"],"is_preprint":false},{"year":2025,"finding":"Inhibition of ACOX1 promotes accumulation of VLCFA-containing cerebrosides, which alter MET and IGF1R interaction with the plasma membrane and selectively inhibit their association with plasma membrane signaling platforms, reducing MET and IGF1R kinase activity in multiple myeloma cells without disrupting membrane platform integrity.","method":"Genetic and pharmacological ACOX1 inhibition, lipidomics (cerebroside accumulation), MET/IGF1R membrane fractionation, kinase activity assays, bortezomib-resistant MM xenograft model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic lipid-kinase connection established by lipidomics and membrane fractionation, in vivo xenograft, single lab","pmids":["39885295"],"is_preprint":false},{"year":2024,"finding":"FXR (farnesoid X receptor) regulates ACOX1 expression: FXR silencing decreases ACOX1 mRNA and protein, while FXR activation with GW4064 increases ACOX1 expression in hepatocytes. Activated ACOX1 correlates with elevated serum LDL, triglycerides, and aggravated hepatic steatosis in FXR-/- mice.","method":"FXR shRNA knockdown, FXR agonist (GW4064) treatment, ACOX1 expression measurement in FXR-/- mice and hepatocyte cell lines","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic and pharmacological FXR manipulation with ACOX1 expression readout, in vivo and in vitro, single lab","pmids":["38595921"],"is_preprint":false},{"year":2025,"finding":"In Acox1 knockout mice, retinal dysfunction is accompanied by reduced mitochondrial number and mitochondrial DNA copy number, decreased retinal pyruvate, and a decrease in ω-3 fatty acids with compensatory increase in ω-6 fatty acids. Nutrient supplementation with pyruvate, DHA (n-3), or DHA plus arachidonic acid (n-6) mitigated retinal dysfunction progression, establishing peroxisomal FAO as essential for retinal metabolic homeostasis.","method":"Global Acox1 KO mice, retinal electrophysiology, proteomics, metabolomics, fatty acid profiling, nutrient supplementation (pyruvate, DHA, AA)","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — global KO with multi-omics and dietary rescue experiments, multiple orthogonal methods, single lab","pmids":["40049514"],"is_preprint":false},{"year":2012,"finding":"siRNA knockdown of ACOX1 in murine oligodendrocytes increases ROS and RNS production even in the absence of VLCFA, and potentiates VLCFA-induced ROS overproduction. Reduced Acox1 levels strongly enhance VLCFA and neutral lipid accumulation in oligodendrocytes both with and without exogenous VLCFA treatment.","method":"siRNA knockdown of Acox1 in 158N oligodendrocytes, ROS/RNS assay, lipid accumulation measurement, SOD/catalase activity assay","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic KD with multiple biochemical readouts in oligodendrocytes, single lab","pmids":["22521832"],"is_preprint":false},{"year":2023,"finding":"ACOX1 is overexpressed in CLL B-lymphocytes and its downmodulation is sufficient to shift CLL cell metabolism from lipid-based to carbon/amino-acid-based oxidative phosphorylation. Complete ACOX1 blockade causes lipid droplet accumulation and caspase-dependent cell death. ACOX1 inhibition combined with BTK inhibitors has a synergistic killing effect on CLL cells.","method":"ACOX1 knockdown, pharmacological ACOX1 inhibition, Seahorse metabolic flux assay, carnitine metabolite profiling, caspase assay, lipid droplet staining, patient CLL samples","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic and pharmacological inhibition with metabolic phenotyping and cell death assays, patient-derived cells, single lab","pmids":["38057495"],"is_preprint":false},{"year":2021,"finding":"C/EBPα transcription factor directly binds the bovine ACOX1 promoter at three sites (-1142 to -1129 bp, -831 to -826 bp, -303 to -298 bp) and inhibits ACOX1 transcription. miR-25-3p directly targets the ACOX1 3'UTR to suppress ACOX1 expression post-transcriptionally. ACOX1 positively regulates bovine intramuscular preadipocyte adipogenesis.","method":"Promoter deletion analysis, site-directed mutagenesis, EMSA, ChIP, dual-luciferase assay, miR-25-3p overexpression, gain/loss-of-function adipogenesis assays","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, luciferase) for transcriptional regulation, bovine ortholog, single lab","pmids":["33502338"],"is_preprint":false},{"year":2024,"finding":"ACOX1 gain-of-function variant p.N237S stabilizes the active ACOX1 dimer (as confirmed in zebrafish model), resulting in dysregulated enzymatic activity, increased oxidative stress, activation of the integrated stress response (ISR), and reduced peroxisome density, leading to motor impairment. The reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate restored swimming ability in mutant zebrafish.","method":"Zebrafish transient overexpression of human ACOX1-N237S-GFP, SKL-targeted mCherry peroxisome reporter, ISR assay, oligodendrocyte counting, antioxidant (dendrimer-NAC) rescue","journal":"Frontiers in pediatrics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo vertebrate model with molecular reporters and antioxidant rescue, single lab","pmids":["38357503"],"is_preprint":false},{"year":2026,"finding":"ACOX1 overexpression increases ROS derived from fatty acid β-oxidation (as shown by mass spectrometry revealing increased FAO), reduces mTOR phosphorylation/activation, and enhances autophagy to suppress colorectal cancer cell proliferation and migration. The pathway was established as ROS→mTOR inhibition→autophagy induction.","method":"ACOX1 overexpression in CRC cells, mass spectrometry (FAO profiling), ROS assay, mTOR phosphorylation (Western blot), autophagy assay, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — overexpression with MS-based metabolic profiling and pathway readouts, in vivo confirmation, single lab","pmids":["39849090"],"is_preprint":false}],"current_model":"ACOX1 is the first and rate-limiting peroxisomal β-oxidation enzyme that catalyzes very-long-chain fatty acid (VLCFA) oxidation generating H2O2; its activity is post-translationally regulated by SIRT5-mediated desuccinylation (inhibitory, suppresses active dimer formation), DUSP14-mediated dephosphorylation (promotes polyubiquitination/proteasomal degradation), OGT-mediated O-GlcNAcylation (protective against ubiquitination), and CLIC1-mediated ubiquitination (promotes degradation); MOXD1 controls ACOX1 peroxisomal trafficking by interacting with the ACOX1–PEX5 translocation complex; transcriptionally, ACOX1 is induced by PPARα (but not as a PPARα/catalase co-regulated gene) and suppressed by C/EBPα and multiple miRNAs (miR-31-5p, miR-222, miR-103-3p, miR-25-3p); gain-of-function variant p.N237S stabilizes the active dimer and elevates ROS causing Schwann cell/glial death via oxidative stress, while loss-of-function causes VLCFA accumulation and peroxisomal dysfunction; ACOX1 substrates include VLCFA, palmitoyl-CoA, and PGE2/arachidonic acid; substrate accumulation upon ACOX1 loss can palmitoylate β-catenin to activate Wnt signaling or accumulate VLCFA-containing cerebrosides to suppress MET/IGF1R membrane signaling; via crotonyl-CoA production ACOX1 also drives HSP90AB1 crotonylation that stabilizes thioredoxin for redox homeostasis in hypoxic cancer cells."},"narrative":{"mechanistic_narrative":"ACOX1 is the first and rate-limiting enzyme of peroxisomal fatty acid β-oxidation, catabolizing very-long-chain fatty acids (VLCFA, including ω-3 C24–C28 species) and generating H2O2 as a byproduct, a function essential for cellular and inter-organ metabolic homeostasis [PMID:38760332, PMID:22521832]. Its peroxisomal import depends on a PTS1 signal recognized by PEX5, and the ACOX1–PEX5 translocation complex is engaged by MOXD1 to control trafficking into peroxisomes [PMID:34270617, PMID:42167911]. Enzyme output is tightly tuned by post-translational regulation: SIRT5-mediated desuccinylation suppresses formation of the catalytically active dimer and lowers H2O2 and oxidative DNA damage [PMID:29491006], DUSP14-mediated dephosphorylation at Ser26 and CLIC1 binding both promote polyubiquitination and proteasomal degradation [PMID:36878899, PMID:41093222], whereas OGT-mediated O-GlcNAcylation shields ACOX1 from K48-linked ubiquitination [PMID:38547945]. Transcriptionally, ACOX1 is induced by PPARα and FXR and repressed by C/EBPα and promoter methylation, with additional post-transcriptional suppression by microRNAs [PMID:40580723, PMID:38595921, PMID:33502338, PMID:38367917]. The dual-edged consequence of its activity is central to disease: loss-of-function drives VLCFA accumulation, peroxisomal dysfunction, and glial/axonal degeneration, while the gain-of-function p.N237S variant stabilizes the active dimer and elevates ROS to cause oxidative-stress neurodegeneration that is reversible by antioxidants [PMID:32169171, PMID:38357503]. Because ACOX1 sits at the junction of lipid catabolism and ROS production, its activity is repeatedly co-opted in cancer—supporting metabolic reprogramming in BRAF-mutant melanoma and CLL persister/tumor cells, and modulating signaling through substrate-dependent effects on β-catenin palmitoylation, PGE2 levels, and crotonyl-CoA-driven protein crotonylation [PMID:33238129, PMID:38057495, PMID:36878899, PMID:29290822, PMID:41675575].","teleology":[{"year":2010,"claim":"Established that human ACOX1 acts through two distinct isoforms with non-redundant roles in restoring VLCFA catabolism and modulating PPARα coactivator recruitment, framing ACOX1 not only as a catabolic enzyme but as a regulator of its own transcriptional axis.","evidence":"Adenoviral ACOX1a/b rescue in Acox1-/- mice with fatty acid profiling and coactivator recruitment assay","pmids":["20195242"],"confidence":"High","gaps":["Did not resolve structural basis for isoform substrate preference","Endogenous PPARα antagonism by nervonoyl-CoA not validated outside liver"]},{"year":2012,"claim":"Showed that reduced ACOX1 raises ROS/RNS and lipid accumulation in oligodendrocytes even without VLCFA challenge, linking ACOX1 loss directly to oxidative stress in glia.","evidence":"siRNA knockdown of Acox1 in 158N oligodendrocytes with ROS/RNS and lipid assays","pmids":["22521832"],"confidence":"Medium","gaps":["Single cell line; in vivo relevance not established here","Source of VLCFA-independent ROS not defined"]},{"year":2018,"claim":"Resolved a key post-translational brake on ACOX1 by showing SIRT5 desuccinylation suppresses active-dimer formation, controlling H2O2 output and genome integrity.","evidence":"Co-IP, deacylase assays, SIRT5 KO mouse liver, and ACOX1-knockdown rescue with succinylation proteomics","pmids":["29491006"],"confidence":"High","gaps":["Specific succinylated lysines governing dimerization not fully mapped","Physiological signals modulating peroxisomal SIRT5 unknown"]},{"year":2019,"claim":"Expanded ACOX1 substrate scope to PGE2 and connected it to apoptotic regulation, showing ACOX1 levels influence cell motility (via PGE2/EP1/ERK/MMP9) and p73-dependent survival.","evidence":"miR-31-5p and ACOX1 manipulation with lipidomics/PGE2 ELISA in OSCC; ACOX1 over/knockdown with caspase and p73 stability assays in lymphoma","pmids":["29290822","31401980"],"confidence":"Medium","gaps":["Direct enzymatic processing of PGE2 vs. indirect effect not biochemically isolated","Mechanism of p73 destabilization by ACOX1 undefined"]},{"year":2020,"claim":"Distinguished two opposite disease mechanisms—loss-of-function VLCFA accumulation versus gain-of-function p.N237S ROS toxicity—establishing ACOX1 dysregulation in either direction as neurodegenerative.","evidence":"Drosophila LOF genetics, patient-derived Schwann cells expressing N237S, ROS assays, antioxidant rescue","pmids":["32169171"],"confidence":"High","gaps":["Structural basis of N237S dimer stabilization not solved in this work","Human therapeutic translation of antioxidant rescue untested"]},{"year":2020,"claim":"Demonstrated ACOX1-driven peroxisomal FAO as a metabolic vulnerability supporting BRAF-inhibitor-tolerant melanoma persister cells, and identified a direct viral target relationship with EV71 RdRp.","evidence":"ACOX1 siRNA and thioridazine inhibition with Seahorse flux and xenografts; Co-IP of EV71 3D with ACOX1 and KD functional readouts","pmids":["33238129","32434419"],"confidence":"Medium","gaps":["Selectivity of peroxisomal FAO inhibition in vivo limited by pharmacology","Functional consequence of 3D–ACOX1 binding for viral replication unresolved"]},{"year":2021,"claim":"Mapped transcriptional repression of ACOX1 by C/EBPα at defined promoter sites and post-transcriptional repression by miR-25-3p, linking ACOX1 dosage to adipogenesis.","evidence":"EMSA, ChIP, promoter mutagenesis, luciferase, and miR-25-3p assays in bovine preadipocytes","pmids":["33502338"],"confidence":"Medium","gaps":["Bovine ortholog; conservation of these elements in human promoter untested","Interplay with PPARα activation not addressed"]},{"year":2021,"claim":"Validated the conserved PTS1/PEX5 import requirement for ACOX1 and its developmental necessity using a nematode ortholog.","evidence":"In vitro/in vivo FAO assays, ACOX-1/PEX-5 Co-IP, PTS1 mutagenesis, RNAi developmental phenotyping in H. contortus","pmids":["34270617"],"confidence":"Medium","gaps":["Demonstrated in nematode ortholog; human import kinetics not measured","Regulatory inputs to import not addressed"]},{"year":2022,"claim":"Defined PPARα as a selective inducer of ACOX1 (distinct from catalase) and placed ACOX1 downstream of a PLA2/COX-2 axis metabolizing arachidonic acid/PGE2.","evidence":"PPARα agonist/withdrawal and PEX16/Pparα double-KO mice; pharmacological PLA2/COX-2/ACOX1 inhibition with TG and PGE2 measurement","pmids":["40580723","35526488"],"confidence":"Medium","gaps":["Direct PPARα binding to ACOX1 promoter not shown in these studies","Quantitative contribution of ACOX1 to PGE2 turnover in vivo uncertain"]},{"year":2023,"claim":"Uncovered a feedforward oncogenic circuit in which DUSP14 dephosphorylates ACOX1 (Ser26) to drive its degradation, and substrate palmitic acid palmitoylates β-catenin to activate Wnt signaling, with β-catenin/c-Myc reinforcing ACOX1 suppression.","evidence":"In vitro dephosphorylation, Co-IP, ubiquitination and palmitoylation assays, S26 mutagenesis, xenografts and CRC clinical samples","pmids":["36878899"],"confidence":"High","gaps":["Kinase counteracting DUSP14 on Ser26 not identified","Generality of the loop beyond colorectal cancer untested"]},{"year":2023,"claim":"Connected epigenetic silencing of ACOX1 to organ fibrosis and identified ACOX1 as a metabolic dependency in CLL B cells.","evidence":"TLR4/NF-κB/DNMT1 promoter-methylation manipulation in renal transplant model; ACOX1 KD/inhibition with Seahorse and cell-death assays in patient CLL cells","pmids":["38367917","38057495"],"confidence":"Medium","gaps":["Direct DNMT1 occupancy at ACOX1 promoter inferred, not fully mapped","Mechanism of metabolic switch upon ACOX1 loss in CLL incompletely defined"]},{"year":2024,"claim":"Established ACOX1 as a hub of an inter-organ axis and a target of stabilizing/destabilizing PTMs and nuclear receptors, linking hepatic ACOX1 output to adipose browning via GPR120 and to FXR/OGT regulation.","evidence":"Liver-specific Acox1 KO with lipidomics and GPR120 signaling; OGT KO and O-GlcNAcylation/ubiquitination assays; FXR silencing/agonism in hepatocytes and FXR-/- mice","pmids":["38760332","38547945","38595921"],"confidence":"High","gaps":["O-GlcNAcylation site on ACOX1 not pinpointed","Direct vs. indirect FXR regulation of ACOX1 unresolved"]},{"year":2025,"claim":"Defined MOXD1 as a trafficking regulator of the ACOX1–PEX5 complex and a druggable node for metabolic liver disease, while extending ACOX1's reach to substrate-driven membrane signaling and crotonylation-based redox control.","evidence":"Co-IP-MS, interface-residue mapping, genetic mouse models and rM15 pharmacology (MASH); lipidomics/membrane fractionation for cerebroside–MET/IGF1R effects; HIF-1α-driven ACOX1, crotonyl-CoA, HSP90AB1 K265 crotonylation, MD simulation and TXN stabilization; DDX1/HNRNPK-mediated ACOX1 alternative splicing; CLIC1-driven ACOX1 degradation","pmids":["42167911","39885295","41675575","41197750","41093222"],"confidence":"Medium","gaps":["Structural model of MOXD1–ACOX1–PEX5 interface based on modelling not experimental structure","Several mechanisms (CLIC1, DDX1 splicing) rest on single-lab data","Direct enzymatic flux producing crotonyl-CoA from ACOX1 not quantified in cells"]},{"year":2025,"claim":"Demonstrated that peroxisomal FAO via ACOX1 is required for retinal metabolic homeostasis and that ACOX1 overexpression drives ROS→mTOR inhibition→autophagy to restrain colorectal cancer growth.","evidence":"Global Acox1 KO mice with multi-omics and dietary rescue; ACOX1 overexpression with MS FAO profiling, mTOR/autophagy readouts and xenografts","pmids":["40049514","39849090"],"confidence":"Medium","gaps":["Tissue-specific contribution of ACOX1 in retina vs. systemic effects not separated","Threshold of ROS distinguishing tumor-suppressive vs. tumor-supportive ACOX1 outcomes undefined"]},{"year":null,"claim":"How the opposing context-dependent outcomes of ACOX1 activity—tumor-suppressive ROS/autophagy versus pro-survival metabolic and redox support—are determined within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling tumor-suppressive and tumor-supportive roles","Quantitative thresholds linking ACOX1-derived H2O2 to distinct downstream pathways unknown","Structural determinants of the active dimer and its regulation by PTMs not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[4,10,21,25]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[4,7,12,17]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0,9,10,14,24]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,5,22,25]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,24,25]}],"complexes":[],"partners":["PEX5","MOXD1","DUSP14","SIRT5","OGT","CLIC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15067","full_name":"Peroxisomal acyl-coenzyme A oxidase 1","aliases":["Palmitoyl-CoA oxidase","Peroxisomal fatty acyl-CoA oxidase","Straight-chain acyl-CoA oxidase","SCOX"],"length_aa":660,"mass_kda":74.4,"function":"Involved in the initial and rate-limiting step of peroxisomal beta-oxidation of straight-chain saturated and unsaturated very-long-chain fatty acids (PubMed:15060085, PubMed:17458872, PubMed:17603022, PubMed:32169171, PubMed:33234382, PubMed:7876265). 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N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/41908884","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.08.25335383","title":"Identification of Key Genes Governing the Effects of Physical Activity on Ferroptosis in Alzheimer’s Disease Patients: A Machine Learning-Based Study","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.25335383","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.10.657506","title":"Decoding Cellular Stress States for Toxicology Using Single-Cell Transcriptomics","date":"2025-06-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.10.657506","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.11.642511","title":"Endothelial  <i>Cept1</i>  Promotes Post-Ischemic Angiogenesis in a  <i>Pparα</i>  -Dependent Fashion","date":"2025-03-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.11.642511","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35048,"output_tokens":7658,"usd":0.110007,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17145,"output_tokens":5143,"usd":0.10715,"stage2_stop_reason":"end_turn"},"total_usd":0.217157,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT5-mediated desuccinylation inhibits ACOX1 enzymatic activity by suppressing its active dimer formation. SIRT5 is present in peroxisomes and ACOX1 is a physiological substrate of SIRT5; deletion of SIRT5 increases ACOX1 succinylation and activity, leading to elevated H2O2 production and oxidative DNA damage that is rescued by ACOX1 knockdown.\",\n      \"method\": \"Co-IP, deacylase activity assay, SIRT5 knockout mouse livers, ACOX1 knockdown rescue experiments, succinylation proteomics\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical interaction, genetic rescue (SIRT5 KO + ACOX1 KD), multiple orthogonal methods in cultured cells and mouse livers\",\n      \"pmids\": [\"29491006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss-of-function mutations in ACOX1 cause glial and axonal loss via accumulation of very-long-chain fatty acids and peroxisomal dysfunction, whereas a gain-of-function variant (p.N237S) causes increased ACOX1 protein levels and elevated reactive oxygen species in glia (Schwann cells/oligodendrocytes), leading to neurodegeneration via a distinct oxidative-stress mechanism. Antioxidant treatment suppressed p.N237S-induced neurodegeneration in flies and primary Schwann cells.\",\n      \"method\": \"Drosophila ACOX1 loss-of-function genetics, patient-derived murine Schwann cells expressing N237S variant, ROS assays, antioxidant rescue experiments\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple model systems (Drosophila genetics, mammalian primary cells, patient samples), mechanistic rescue experiments, two distinct mutational mechanisms established\",\n      \"pmids\": [\"32169171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DUSP14 phosphatase dephosphorylates ACOX1 at serine 26, promoting its polyubiquitination and proteasomal degradation. Loss of ACOX1 leads to accumulation of its substrate palmitic acid (PA), which palmitoylates β-catenin at cysteine 466, blocking CK1/GSK3-directed phosphorylation and β-TrCP-mediated degradation of β-catenin, thereby stabilizing β-catenin and activating Wnt signaling to promote colorectal cancer progression. Stabilized β-catenin in turn transcriptionally represses ACOX1 and activates DUSP14 via c-Myc, forming a feedforward loop.\",\n      \"method\": \"In vitro dephosphorylation assay, co-IP, ubiquitination assay, site-directed mutagenesis (S26), palmitoylation assay, mouse xenograft models, patient-derived xenograft experiments, CRC clinical samples\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods (in vitro assay, mutagenesis, co-IP, palmitoylation assay), in vivo models, and clinical validation in one study\",\n      \"pmids\": [\"36878899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human ACOX1 has two isoforms (ACOX1a and ACOX1b) from a single gene; ACOX1b is markedly more effective than ACOX1a in reversing the Acox1-null hepatic phenotype in mice. ACOX1b expression restores nervonic acid production, which negatively impacts recruitment of coactivators to the PPARα-response unit (suggesting nervonic acid/nervonoyl-CoA as endogenous PPARα antagonist). Restoration of DHA requires concomitant expression of both isoforms.\",\n      \"method\": \"Adenoviral ACOX1a/b expression in Acox1-/- mice, fatty acid profiling, PPARα coactivator recruitment assay, liver phenotype analysis\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic rescue experiment with two isoforms, fatty acid profiling, and transcriptional coactivator recruitment assay in Acox1 knockout mice\",\n      \"pmids\": [\"20195242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatic ACOX1-mediated peroxisomal β-oxidation catabolizes very-long-chain fatty acids (VLCFA, C24–C28 ω-3 species); liver-specific Acox1 knockout increases circulating ω-3 VLCFAs that promote adipose browning, mitochondrial biogenesis, and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes, establishing an inter-organ communication axis regulating metabolic homeostasis.\",\n      \"method\": \"Liver-specific Acox1 knockout mice, serum lipidomics, white adipocyte browning assay, GPR120 signaling assay, conditioned serum experiments on cultured adipocytes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — liver-specific KO with lipidomics, mechanistic receptor identification (GPR120), multiple orthogonal functional readouts in vitro and in vivo\",\n      \"pmids\": [\"38760332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACOX1 is the key peroxisomal fatty acid β-oxidation enzyme supporting metabolic reprogramming from glycolysis to oxidative respiration in BRAF(V600E) melanoma persister cells tolerant to BRAF/MEK inhibitors. Knockdown of ACOX1 or treatment with the peroxisomal FAO inhibitor thioridazine specifically suppresses oxidative respiration of persister cells and decreases their emergence. PPARα transcriptionally regulates this FAO program.\",\n      \"method\": \"ACOX1 siRNA knockdown, thioridazine pharmacological inhibition, Seahorse metabolic flux assay, mouse xenograft experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KD and pharmacological inhibition with orthogonal metabolic readouts, in vivo mouse model confirmation\",\n      \"pmids\": [\"33238129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"O-GlcNAcylation by OGT (O-GlcNAc transferase) protects ACOX1 from ubiquitination-dependent proteasomal degradation. The OGT-ACOX1 interaction at the K48 site precludes K48-linked ubiquitination; deletion of O-GlcNAcylation disrupts lipid metabolism with accumulation of medium- and long-chain fatty acids.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, OGT knockout mice, in vitro lipid metabolism analysis, AML-12 cell OGT inhibitor treatment\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP interaction and ubiquitination assay shown, single lab, mechanistic follow-up in cells and mice\",\n      \"pmids\": [\"38547945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ACOX1 processes prostaglandin E2 (PGE2) as a substrate; the miR-31-5p–ACOX1 axis controls extracellular PGE2 levels in OSCC cells, modulating cell migration and invasion through EP1–ERK–MMP9 signaling. miR-31-5p directly suppresses ACOX1 expression, leading to PGE2 accumulation and enhanced cell motility.\",\n      \"method\": \"miR-31-5p overexpression/knockdown, ACOX1 knockdown, lipidomics, PGE2 ELISA, migration/invasion assays, EP1/ERK/MMP9 pathway analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct manipulation of ACOX1 and miR-31-5p with lipidomic substrate profiling and downstream signaling, single lab\",\n      \"pmids\": [\"29290822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ACOX1 overexpression in lymphoma cells destabilizes p73 protein (but not p53), reducing p73 expression. Downregulation of ACOX1 promotes mitochondrial translocation of Bad, reduces mitochondrial membrane potential, and activates caspase-9 and caspase-3-dependent apoptosis. p73 expression is required for the apoptotic induction seen upon ACOX1 knockdown.\",\n      \"method\": \"ACOX1 overexpression/knockdown, caspase activity assay, mitochondrial membrane potential assay, mitochondrial fractionation (Bad localization), p73 stability assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple cell biology assays establishing pathway, single lab, single cancer type\",\n      \"pmids\": [\"31401980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EV71 non-structural protein 3D (RdRp) directly interacts with ACOX1 protein and promotes ACOX1 downregulation. ACOX1 knockdown alone induces apoptosis and autophagy in neural cells, reduces peroxisome numbers, increases ROS, and attenuates the DJ-1/NRF2/HO-1 cytoprotective pathway.\",\n      \"method\": \"Co-IP (3D–ACOX1 interaction), ACOX1 siRNA knockdown, peroxisome counting, ROS assay, apoptosis/autophagy assays, NRF2/HO-1 pathway analysis\",\n      \"journal\": \"Virulence\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct co-IP for viral protein–ACOX1 interaction, genetic KD with multiple functional readouts, single lab\",\n      \"pmids\": [\"32434419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Haemonchus contortus (parasitic nematode), ACOX1 proteins show fatty acid oxidation activity in vitro and in vivo and interact with the peroxisomal targeting receptor PEX-5 via a peroxisomal targeting signal type 1 (PTS1) sequence. PTS1 is required for ACOX-1 recognition by PEX-5. Knockdown of acox-1 impairs post-embryonic larval development.\",\n      \"method\": \"In vitro and in vivo fatty acid oxidation assay, co-IP (ACOX-1/PEX-5), PTS1 mutagenesis, RNAi knockdown, developmental phenotyping\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution of enzymatic activity, co-IP with PTS1 mutagenesis validation, single organism/lab (nematode ortholog)\",\n      \"pmids\": [\"34270617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PPARα transcriptionally regulates ACOX1 mRNA and protein expression (but not catalase). PPARα agonist WY-14,643 induces ACOX1 to a greater extent than catalase; after agonist withdrawal, ACOX1 returns to baseline faster. In liver-specific PEX16 knockout (peroxisome-absent) mice crossed with Pparα-/- mice, upregulated ACOX1 protein is suppressed by PPARα ablation, while catalase remains elevated.\",\n      \"method\": \"PPARα agonist/withdrawal experiments, liver-specific PEX16 KO and Pparα-/- double-KO mice, mRNA and protein quantification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout (double KO model) with mRNA and protein evidence, single lab\",\n      \"pmids\": [\"40580723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PPARα agonist WY-14,643 induces a PLA2/COX-2/ACOX1 pathway in which arachidonic acid (AA) released by PLA2 from phospholipids is metabolized by ACOX1 (oxidizing PGE2). ACOX1-specific inhibitor restores both WY-14,643-suppressed liver TG and PGE2 levels, establishing that ACOX1 oxidizes PGE2/AA as substrates downstream of the PLA2/COX-2 axis in peroxisomal FAO.\",\n      \"method\": \"PPARα agonist treatment in mice (liquid diet), ACOX1-specific inhibitor (10,12-tricosadiynoic acid), COX-2 inhibitor, liver TG and PGE2 measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological pathway dissection with specific inhibitors and metabolite quantification, single lab\",\n      \"pmids\": [\"35526488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACOX1 downregulation in renal allografts is induced by TLR4–NF-κB signaling via DNA methyltransferase 1 (DNMT1)-dependent promoter methylation. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), promoting epithelial-mesenchymal transition (EMT) and extracellular matrix reorganization via endoplasmic reticulum (ER) stress, causing fibrosis.\",\n      \"method\": \"TLR4/NF-κB pathway manipulation, DNMT1 inhibition, ACOX1 KD/KO in renal cells, ER stress assay, EMT/ECM markers, rat renal transplant model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple pathway interventions in vitro and in vivo rat model, single lab\",\n      \"pmids\": [\"38367917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MOXD1 directly interacts with the ACOX1–PEX5 translocation complex, promoting ACOX1 trafficking to peroxisomes and blocking lipolysis/lipophagy. Four key MOXD1 residues required for ACOX1 binding were identified. A small molecule (rM15) that directly binds MOXD1 and blocks its interaction with ACOX1 reduces hepatocyte lipid accumulation and suppresses diet-induced MASH in vivo.\",\n      \"method\": \"Co-IP mass spectrometry, structural modelling, colocalization analysis, hepatocyte-specific transgenic/KO mice, AAV8 knockdown model, small molecule screening and in vitro/in vivo pharmacology\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP-MS identifying interaction, structural modelling identifying interface residues, multiple genetic models, in vivo pharmacological validation\",\n      \"pmids\": [\"42167911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLIC1 protein binds ACOX1 protein, reduces ACOX1 stability, and facilitates its polyubiquitination-dependent proteasomal degradation, thereby decreasing ACOX1 levels and enhancing cellular oxidative stress to promote gastric cancer progression.\",\n      \"method\": \"Co-IP (CLIC1–ACOX1), ubiquitination assay, ACOX1 knockdown/overexpression, oxidative stress assay, gastric cancer cell proliferation/migration assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction with ubiquitination assay, single lab, functional phenotype established\",\n      \"pmids\": [\"41093222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Glucose starvation induces crotonylation of DDX1 (DEAD-box helicase 1) at lysine 490 (regulated by crotonyltransferase GCN5 and decrotonylase HDAC1), enhancing DDX1 interaction with HNRNPK, which mediates mutually exclusive alternative splicing of ACOX1. The resulting ACOX1 splice variant promotes peroxisomal ROS generation, enhancing oxidative damage and suppressing colorectal cancer cell proliferation.\",\n      \"method\": \"Crotonylation site mapping, DDX1 K490 mutagenesis, HNRNPK co-IP, ACOX1 alternative splicing analysis (RT-PCR/RNA-seq), ROS assay, CRC cell proliferation assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — PTM site mapping with mutagenesis, co-IP, splicing analysis, functional ROS/proliferation readouts, single lab\",\n      \"pmids\": [\"41197750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hypoxia induces HIF-1α-dependent transcriptional upregulation of ACOX1, which increases crotonyl-CoA levels driving site-specific crotonylation of HSP90AB1 at lysine 265. K265 crotonylation induces conformational compaction of HSP90AB1, strengthening its interaction with thioredoxin (TXN) and enhancing TXN stability to buffer ROS. Pharmacological inhibition of ACOX1 (10,12-tricosadiynoic acid) or K265R mutagenesis disrupts this axis and synergizes with cisplatin to suppress tumor growth.\",\n      \"method\": \"HIF-1α manipulation, ACOX1 inhibitor treatment, HSP90AB1 K265 mutagenesis, crotonylation proteomics, molecular dynamics simulation, co-IP (HSP90AB1–TXN), in vivo tumor xenograft\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM site mutagenesis, molecular dynamics, co-IP, pharmacological inhibition with in vivo validation, single lab\",\n      \"pmids\": [\"41675575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Inhibition of ACOX1 promotes accumulation of VLCFA-containing cerebrosides, which alter MET and IGF1R interaction with the plasma membrane and selectively inhibit their association with plasma membrane signaling platforms, reducing MET and IGF1R kinase activity in multiple myeloma cells without disrupting membrane platform integrity.\",\n      \"method\": \"Genetic and pharmacological ACOX1 inhibition, lipidomics (cerebroside accumulation), MET/IGF1R membrane fractionation, kinase activity assays, bortezomib-resistant MM xenograft model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic lipid-kinase connection established by lipidomics and membrane fractionation, in vivo xenograft, single lab\",\n      \"pmids\": [\"39885295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FXR (farnesoid X receptor) regulates ACOX1 expression: FXR silencing decreases ACOX1 mRNA and protein, while FXR activation with GW4064 increases ACOX1 expression in hepatocytes. Activated ACOX1 correlates with elevated serum LDL, triglycerides, and aggravated hepatic steatosis in FXR-/- mice.\",\n      \"method\": \"FXR shRNA knockdown, FXR agonist (GW4064) treatment, ACOX1 expression measurement in FXR-/- mice and hepatocyte cell lines\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic and pharmacological FXR manipulation with ACOX1 expression readout, in vivo and in vitro, single lab\",\n      \"pmids\": [\"38595921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Acox1 knockout mice, retinal dysfunction is accompanied by reduced mitochondrial number and mitochondrial DNA copy number, decreased retinal pyruvate, and a decrease in ω-3 fatty acids with compensatory increase in ω-6 fatty acids. Nutrient supplementation with pyruvate, DHA (n-3), or DHA plus arachidonic acid (n-6) mitigated retinal dysfunction progression, establishing peroxisomal FAO as essential for retinal metabolic homeostasis.\",\n      \"method\": \"Global Acox1 KO mice, retinal electrophysiology, proteomics, metabolomics, fatty acid profiling, nutrient supplementation (pyruvate, DHA, AA)\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — global KO with multi-omics and dietary rescue experiments, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40049514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"siRNA knockdown of ACOX1 in murine oligodendrocytes increases ROS and RNS production even in the absence of VLCFA, and potentiates VLCFA-induced ROS overproduction. Reduced Acox1 levels strongly enhance VLCFA and neutral lipid accumulation in oligodendrocytes both with and without exogenous VLCFA treatment.\",\n      \"method\": \"siRNA knockdown of Acox1 in 158N oligodendrocytes, ROS/RNS assay, lipid accumulation measurement, SOD/catalase activity assay\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic KD with multiple biochemical readouts in oligodendrocytes, single lab\",\n      \"pmids\": [\"22521832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACOX1 is overexpressed in CLL B-lymphocytes and its downmodulation is sufficient to shift CLL cell metabolism from lipid-based to carbon/amino-acid-based oxidative phosphorylation. Complete ACOX1 blockade causes lipid droplet accumulation and caspase-dependent cell death. ACOX1 inhibition combined with BTK inhibitors has a synergistic killing effect on CLL cells.\",\n      \"method\": \"ACOX1 knockdown, pharmacological ACOX1 inhibition, Seahorse metabolic flux assay, carnitine metabolite profiling, caspase assay, lipid droplet staining, patient CLL samples\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic and pharmacological inhibition with metabolic phenotyping and cell death assays, patient-derived cells, single lab\",\n      \"pmids\": [\"38057495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C/EBPα transcription factor directly binds the bovine ACOX1 promoter at three sites (-1142 to -1129 bp, -831 to -826 bp, -303 to -298 bp) and inhibits ACOX1 transcription. miR-25-3p directly targets the ACOX1 3'UTR to suppress ACOX1 expression post-transcriptionally. ACOX1 positively regulates bovine intramuscular preadipocyte adipogenesis.\",\n      \"method\": \"Promoter deletion analysis, site-directed mutagenesis, EMSA, ChIP, dual-luciferase assay, miR-25-3p overexpression, gain/loss-of-function adipogenesis assays\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, luciferase) for transcriptional regulation, bovine ortholog, single lab\",\n      \"pmids\": [\"33502338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACOX1 gain-of-function variant p.N237S stabilizes the active ACOX1 dimer (as confirmed in zebrafish model), resulting in dysregulated enzymatic activity, increased oxidative stress, activation of the integrated stress response (ISR), and reduced peroxisome density, leading to motor impairment. The reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate restored swimming ability in mutant zebrafish.\",\n      \"method\": \"Zebrafish transient overexpression of human ACOX1-N237S-GFP, SKL-targeted mCherry peroxisome reporter, ISR assay, oligodendrocyte counting, antioxidant (dendrimer-NAC) rescue\",\n      \"journal\": \"Frontiers in pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo vertebrate model with molecular reporters and antioxidant rescue, single lab\",\n      \"pmids\": [\"38357503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ACOX1 overexpression increases ROS derived from fatty acid β-oxidation (as shown by mass spectrometry revealing increased FAO), reduces mTOR phosphorylation/activation, and enhances autophagy to suppress colorectal cancer cell proliferation and migration. The pathway was established as ROS→mTOR inhibition→autophagy induction.\",\n      \"method\": \"ACOX1 overexpression in CRC cells, mass spectrometry (FAO profiling), ROS assay, mTOR phosphorylation (Western blot), autophagy assay, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — overexpression with MS-based metabolic profiling and pathway readouts, in vivo confirmation, single lab\",\n      \"pmids\": [\"39849090\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACOX1 is the first and rate-limiting peroxisomal β-oxidation enzyme that catalyzes very-long-chain fatty acid (VLCFA) oxidation generating H2O2; its activity is post-translationally regulated by SIRT5-mediated desuccinylation (inhibitory, suppresses active dimer formation), DUSP14-mediated dephosphorylation (promotes polyubiquitination/proteasomal degradation), OGT-mediated O-GlcNAcylation (protective against ubiquitination), and CLIC1-mediated ubiquitination (promotes degradation); MOXD1 controls ACOX1 peroxisomal trafficking by interacting with the ACOX1–PEX5 translocation complex; transcriptionally, ACOX1 is induced by PPARα (but not as a PPARα/catalase co-regulated gene) and suppressed by C/EBPα and multiple miRNAs (miR-31-5p, miR-222, miR-103-3p, miR-25-3p); gain-of-function variant p.N237S stabilizes the active dimer and elevates ROS causing Schwann cell/glial death via oxidative stress, while loss-of-function causes VLCFA accumulation and peroxisomal dysfunction; ACOX1 substrates include VLCFA, palmitoyl-CoA, and PGE2/arachidonic acid; substrate accumulation upon ACOX1 loss can palmitoylate β-catenin to activate Wnt signaling or accumulate VLCFA-containing cerebrosides to suppress MET/IGF1R membrane signaling; via crotonyl-CoA production ACOX1 also drives HSP90AB1 crotonylation that stabilizes thioredoxin for redox homeostasis in hypoxic cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACOX1 is the first and rate-limiting enzyme of peroxisomal fatty acid β-oxidation, catabolizing very-long-chain fatty acids (VLCFA, including ω-3 C24–C28 species) and generating H2O2 as a byproduct, a function essential for cellular and inter-organ metabolic homeostasis [#4, #21]. Its peroxisomal import depends on a PTS1 signal recognized by PEX5, and the ACOX1–PEX5 translocation complex is engaged by MOXD1 to control trafficking into peroxisomes [#10, #14]. Enzyme output is tightly tuned by post-translational regulation: SIRT5-mediated desuccinylation suppresses formation of the catalytically active dimer and lowers H2O2 and oxidative DNA damage [#0], DUSP14-mediated dephosphorylation at Ser26 and CLIC1 binding both promote polyubiquitination and proteasomal degradation [#2, #15], whereas OGT-mediated O-GlcNAcylation shields ACOX1 from K48-linked ubiquitination [#6]. Transcriptionally, ACOX1 is induced by PPARα and FXR and repressed by C/EBPα and promoter methylation, with additional post-transcriptional suppression by microRNAs [#11, #19, #23, #13]. The dual-edged consequence of its activity is central to disease: loss-of-function drives VLCFA accumulation, peroxisomal dysfunction, and glial/axonal degeneration, while the gain-of-function p.N237S variant stabilizes the active dimer and elevates ROS to cause oxidative-stress neurodegeneration that is reversible by antioxidants [#1, #24]. Because ACOX1 sits at the junction of lipid catabolism and ROS production, its activity is repeatedly co-opted in cancer—supporting metabolic reprogramming in BRAF-mutant melanoma and CLL persister/tumor cells, and modulating signaling through substrate-dependent effects on β-catenin palmitoylation, PGE2 levels, and crotonyl-CoA-driven protein crotonylation [#5, #22, #2, #7, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that human ACOX1 acts through two distinct isoforms with non-redundant roles in restoring VLCFA catabolism and modulating PPARα coactivator recruitment, framing ACOX1 not only as a catabolic enzyme but as a regulator of its own transcriptional axis.\",\n      \"evidence\": \"Adenoviral ACOX1a/b rescue in Acox1-/- mice with fatty acid profiling and coactivator recruitment assay\",\n      \"pmids\": [\"20195242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve structural basis for isoform substrate preference\", \"Endogenous PPARα antagonism by nervonoyl-CoA not validated outside liver\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that reduced ACOX1 raises ROS/RNS and lipid accumulation in oligodendrocytes even without VLCFA challenge, linking ACOX1 loss directly to oxidative stress in glia.\",\n      \"evidence\": \"siRNA knockdown of Acox1 in 158N oligodendrocytes with ROS/RNS and lipid assays\",\n      \"pmids\": [\"22521832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line; in vivo relevance not established here\", \"Source of VLCFA-independent ROS not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved a key post-translational brake on ACOX1 by showing SIRT5 desuccinylation suppresses active-dimer formation, controlling H2O2 output and genome integrity.\",\n      \"evidence\": \"Co-IP, deacylase assays, SIRT5 KO mouse liver, and ACOX1-knockdown rescue with succinylation proteomics\",\n      \"pmids\": [\"29491006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific succinylated lysines governing dimerization not fully mapped\", \"Physiological signals modulating peroxisomal SIRT5 unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded ACOX1 substrate scope to PGE2 and connected it to apoptotic regulation, showing ACOX1 levels influence cell motility (via PGE2/EP1/ERK/MMP9) and p73-dependent survival.\",\n      \"evidence\": \"miR-31-5p and ACOX1 manipulation with lipidomics/PGE2 ELISA in OSCC; ACOX1 over/knockdown with caspase and p73 stability assays in lymphoma\",\n      \"pmids\": [\"29290822\", \"31401980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic processing of PGE2 vs. indirect effect not biochemically isolated\", \"Mechanism of p73 destabilization by ACOX1 undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Distinguished two opposite disease mechanisms—loss-of-function VLCFA accumulation versus gain-of-function p.N237S ROS toxicity—establishing ACOX1 dysregulation in either direction as neurodegenerative.\",\n      \"evidence\": \"Drosophila LOF genetics, patient-derived Schwann cells expressing N237S, ROS assays, antioxidant rescue\",\n      \"pmids\": [\"32169171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of N237S dimer stabilization not solved in this work\", \"Human therapeutic translation of antioxidant rescue untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated ACOX1-driven peroxisomal FAO as a metabolic vulnerability supporting BRAF-inhibitor-tolerant melanoma persister cells, and identified a direct viral target relationship with EV71 RdRp.\",\n      \"evidence\": \"ACOX1 siRNA and thioridazine inhibition with Seahorse flux and xenografts; Co-IP of EV71 3D with ACOX1 and KD functional readouts\",\n      \"pmids\": [\"33238129\", \"32434419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity of peroxisomal FAO inhibition in vivo limited by pharmacology\", \"Functional consequence of 3D–ACOX1 binding for viral replication unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped transcriptional repression of ACOX1 by C/EBPα at defined promoter sites and post-transcriptional repression by miR-25-3p, linking ACOX1 dosage to adipogenesis.\",\n      \"evidence\": \"EMSA, ChIP, promoter mutagenesis, luciferase, and miR-25-3p assays in bovine preadipocytes\",\n      \"pmids\": [\"33502338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bovine ortholog; conservation of these elements in human promoter untested\", \"Interplay with PPARα activation not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Validated the conserved PTS1/PEX5 import requirement for ACOX1 and its developmental necessity using a nematode ortholog.\",\n      \"evidence\": \"In vitro/in vivo FAO assays, ACOX-1/PEX-5 Co-IP, PTS1 mutagenesis, RNAi developmental phenotyping in H. contortus\",\n      \"pmids\": [\"34270617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in nematode ortholog; human import kinetics not measured\", \"Regulatory inputs to import not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined PPARα as a selective inducer of ACOX1 (distinct from catalase) and placed ACOX1 downstream of a PLA2/COX-2 axis metabolizing arachidonic acid/PGE2.\",\n      \"evidence\": \"PPARα agonist/withdrawal and PEX16/Pparα double-KO mice; pharmacological PLA2/COX-2/ACOX1 inhibition with TG and PGE2 measurement\",\n      \"pmids\": [\"40580723\", \"35526488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PPARα binding to ACOX1 promoter not shown in these studies\", \"Quantitative contribution of ACOX1 to PGE2 turnover in vivo uncertain\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a feedforward oncogenic circuit in which DUSP14 dephosphorylates ACOX1 (Ser26) to drive its degradation, and substrate palmitic acid palmitoylates β-catenin to activate Wnt signaling, with β-catenin/c-Myc reinforcing ACOX1 suppression.\",\n      \"evidence\": \"In vitro dephosphorylation, Co-IP, ubiquitination and palmitoylation assays, S26 mutagenesis, xenografts and CRC clinical samples\",\n      \"pmids\": [\"36878899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase counteracting DUSP14 on Ser26 not identified\", \"Generality of the loop beyond colorectal cancer untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected epigenetic silencing of ACOX1 to organ fibrosis and identified ACOX1 as a metabolic dependency in CLL B cells.\",\n      \"evidence\": \"TLR4/NF-κB/DNMT1 promoter-methylation manipulation in renal transplant model; ACOX1 KD/inhibition with Seahorse and cell-death assays in patient CLL cells\",\n      \"pmids\": [\"38367917\", \"38057495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNMT1 occupancy at ACOX1 promoter inferred, not fully mapped\", \"Mechanism of metabolic switch upon ACOX1 loss in CLL incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ACOX1 as a hub of an inter-organ axis and a target of stabilizing/destabilizing PTMs and nuclear receptors, linking hepatic ACOX1 output to adipose browning via GPR120 and to FXR/OGT regulation.\",\n      \"evidence\": \"Liver-specific Acox1 KO with lipidomics and GPR120 signaling; OGT KO and O-GlcNAcylation/ubiquitination assays; FXR silencing/agonism in hepatocytes and FXR-/- mice\",\n      \"pmids\": [\"38760332\", \"38547945\", \"38595921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"O-GlcNAcylation site on ACOX1 not pinpointed\", \"Direct vs. indirect FXR regulation of ACOX1 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined MOXD1 as a trafficking regulator of the ACOX1–PEX5 complex and a druggable node for metabolic liver disease, while extending ACOX1's reach to substrate-driven membrane signaling and crotonylation-based redox control.\",\n      \"evidence\": \"Co-IP-MS, interface-residue mapping, genetic mouse models and rM15 pharmacology (MASH); lipidomics/membrane fractionation for cerebroside–MET/IGF1R effects; HIF-1α-driven ACOX1, crotonyl-CoA, HSP90AB1 K265 crotonylation, MD simulation and TXN stabilization; DDX1/HNRNPK-mediated ACOX1 alternative splicing; CLIC1-driven ACOX1 degradation\",\n      \"pmids\": [\"42167911\", \"39885295\", \"41675575\", \"41197750\", \"41093222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model of MOXD1–ACOX1–PEX5 interface based on modelling not experimental structure\", \"Several mechanisms (CLIC1, DDX1 splicing) rest on single-lab data\", \"Direct enzymatic flux producing crotonyl-CoA from ACOX1 not quantified in cells\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that peroxisomal FAO via ACOX1 is required for retinal metabolic homeostasis and that ACOX1 overexpression drives ROS→mTOR inhibition→autophagy to restrain colorectal cancer growth.\",\n      \"evidence\": \"Global Acox1 KO mice with multi-omics and dietary rescue; ACOX1 overexpression with MS FAO profiling, mTOR/autophagy readouts and xenografts\",\n      \"pmids\": [\"40049514\", \"39849090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific contribution of ACOX1 in retina vs. systemic effects not separated\", \"Threshold of ROS distinguishing tumor-suppressive vs. tumor-supportive ACOX1 outcomes undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the opposing context-dependent outcomes of ACOX1 activity—tumor-suppressive ROS/autophagy versus pro-survival metabolic and redox support—are determined within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling tumor-suppressive and tumor-supportive roles\", \"Quantitative thresholds linking ACOX1-derived H2O2 to distinct downstream pathways unknown\", \"Structural determinants of the active dimer and its regulation by PTMs not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [4, 10, 21, 25]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [4, 7, 12, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 9, 10, 14, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 5, 22, 25]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 24, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PEX5\", \"MOXD1\", \"DUSP14\", \"SIRT5\", \"OGT\", \"CLIC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}