{"gene":"DECR1","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":1997,"finding":"Human DECR1 encodes the 120-kDa isoform of mitochondrial 2,4-dienoyl-CoA reductase (EC 1.3.1.34), an auxiliary enzyme of β-oxidation that participates in the metabolism of unsaturated fatty enoyl-CoA esters having double bonds in both even- and odd-numbered positions. The gene comprises 10 exons, lacks a TATA box, and was mapped to chromosomal band 8q21.3 by FISH.","method":"Molecular cloning, primer extension, 5' RACE-PCR, FISH on metaphase chromosomes","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct molecular cloning, enzymatic characterization (EC number assignment), and chromosomal localization by FISH in a single focused study","pmids":["9403065"],"is_preprint":false},{"year":2007,"finding":"Ectopic expression of catalytically impaired DecR1 mutants (vs. wild-type) in ErbB2/Neu-transformed breast cancer cells restored Neu expression and increased mammary tumorigenesis in vivo, demonstrating that DECR1's enzymatic activity is required for its tumor-suppressive effects, including reduction of de novo fatty acid synthesis rates and suppression of ErbB2/Neu expression.","method":"Catalytic mutant expression, in vivo xenograft tumorigenic assays, de novo fatty acid synthesis measurements, proliferation index assessment","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — active-site mutagenesis combined with in vivo functional readouts and biochemical de novo lipid synthesis assay in a single study","pmids":["17636013"],"is_preprint":false},{"year":2020,"finding":"DECR1 is the rate-limiting enzyme for β-oxidation of polyunsaturated fatty acids (PUFAs) in prostate cancer cells. DECR1 knockdown selectively inhibited PUFA β-oxidation, caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. DECR1 is a negatively-regulated androgen receptor (AR) target gene.","method":"siRNA knockdown, β-oxidation flux assays, lipid peroxidation/ROS measurement, mouse xenograft models, ex vivo clinical tumor culture, androgen receptor ChIP/regulation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (flux assay, lipid peroxidation, in vivo models, AR regulation), replicated across multiple cell lines and clinical samples","pmids":["32686647"],"is_preprint":false},{"year":2019,"finding":"Decr-deficient (Decr-/-) mice display intact β-oxidation of saturated fatty acids but blunted breakdown of unsaturated fatty acids, leading to failure of brown adipose tissue (BAT) thermogenesis upon cold challenge due to accumulation of unsaturated long-chain fatty acids/metabolites that suppress downstream norepinephrine (NE) signaling, despite functional NE signaling and inappropriate thermogenic gene expression.","method":"Decr knockout mouse model, indirect calorimetry, thermography, MRI, electron microscopy, mass spectrometry, biochemical lipolysis assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse with multiple orthogonal phenotypic and biochemical readouts in a single focused study","pmids":["31427678"],"is_preprint":false},{"year":2021,"finding":"DECR1 directly interacts with hormone-sensitive lipase (HSL), and this interaction increases HSL phosphorylation and activity, facilitating translocation of HSL to lipid droplets, thereby promoting lipolysis and release of free fatty acids to support cervical cancer cell migration and growth.","method":"Co-immunoprecipitation, DECR1 overexpression/silencing, TAG content measurement, HSL phosphorylation and activity assays, lipid droplet translocation imaging","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and functional assays in a single lab, multiple readouts but no structural or in vitro reconstitution","pmids":["34896618"],"is_preprint":false},{"year":2023,"finding":"Mouse (but not human or Drosophila) Decr1 forms a high-affinity complex with 2'-5' oligoadenylates (OAs), innate immune signaling nucleotides. A 1.4 Å co-crystal structure of mouse Decr1 bound to 2'-5' OA revealed the structural basis of high-affinity recognition and the mechanism of species specificity. No profound antiviral function of Decr1 or 2'-5' OA-dependent regulation through Decr1 was identified.","method":"Mass spectrometry pull-down, biochemical binding characterization, 1.4 Å co-crystal structure","journal":"The Journal of general virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure with biochemical binding validation; negative functional finding explicitly noted","pmids":["37676257"],"is_preprint":false},{"year":2024,"finding":"BMP9 increases the expression of mitochondrial DECR1 in the heart, promoting cardiac mitochondrial bioenergetics and mitigating myocardial infarction-induced cardiomyocyte injury. DECR1 deficiency exacerbates MI-induced cardiac damage, and this adverse effect is restored by AAV-mediated DECR1 re-expression. DECR1 deletion abrogates the cardioprotective effect of BMP9.","method":"AAV-mediated gene expression/knockdown in mouse MI models, cardiac function assessment (echocardiography), DECR1 KO mice, recombinant BMP9 treatment, immunoblot","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic rescue experiments with functional cardiac readouts, single lab, no biochemical mechanism of BMP9→DECR1 regulation defined","pmids":["39315433"],"is_preprint":false},{"year":2024,"finding":"Bufalin promotes degradation of DECR1 via autophagy and ubiquitination pathways. DECR1 interacts with SLC7A11; inhibition of SLC7A11 decreases DECR1 expression. DECR1 overexpression reverses bufalin-induced ferroptosis (accumulation of MDA, ROS, Fe2+; downregulation of SLC7A11, GPX4), establishing a DECR1-SLC7A11 axis in breast cancer ferroptosis regulation.","method":"High-content screening, molecular docking, Co-immunoprecipitation (DECR1-SLC7A11 interaction), autophagy/ubiquitination inhibitor assays, DECR1 overexpression rescue, in vivo tumor models","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction, multiple functional assays with rescue, single lab; structural mechanism not established","pmids":["39427521"],"is_preprint":false},{"year":2025,"finding":"DECR1 interacts with and upregulates pyruvate dehydrogenase kinase 4 (PDK4) in injured cardiomyocytes. PDK4 acts as a kinase that induces phosphorylation and mitochondrial translocation of HDAC3. In mitochondria, HDAC3 mediates deacetylation of HADHA (dehydrogenase trifunctional multienzyme complex α subunit), contributing to excessive mitochondrial FAO and cardiac injury in diabetic cardiomyopathy.","method":"RNA sequencing, gain/loss-of-function (cardiomyocyte-specific KD/OE), Co-immunoprecipitation (DECR1-PDK4), PDK4 overexpression epistasis rescue experiments, neonatal rat cardiomyocyte HG/HP model, T2D mouse model","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for DECR1-PDK4, epistasis via PDK4 OE rescue, multiple functional readouts, single lab","pmids":["40052435"],"is_preprint":false},{"year":2025,"finding":"DECR1 knockdown in breast cancer cells inhibits production of arachidonic acid (AA) with phosphatidylcholine (PC) accumulation, elevates PLA2G12A expression, increases ACSL4, and decreases GPX4/SLC7A11, inducing ferroptosis via a PC/AA metabolic axis.","method":"siRNA knockdown, multi-omics (transcriptomic + lipidomic), metabolite detection, western blotting, virtual screening for inhibitor Erigoster B","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics with metabolite validation and functional ferroptosis readouts, single lab","pmids":["40467779"],"is_preprint":false},{"year":2026,"finding":"GIPC1 directly binds DECR1 via its PDZ domain (KD = 16.3 nM by SPR) and facilitates actin-dependent transport of DECR1 into mitochondria. GIPC1 deficiency reduces DECR1 mitochondrial localization, increases PUFA-containing phospholipids, and promotes ferroptosis; DECR1 overexpression rescues GIPC1 ablation-induced ferroptosis.","method":"Co-IP/MS, molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation, immunofluorescence colocalization, GIPC1 cardiac-specific KO mouse, proteomic + lipidomic analysis, DECR1 OE rescue","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SPR quantitative binding (KD), Co-IP/MS, IF localization, in vivo KO with rescue, multiple orthogonal methods in single study","pmids":["41787053"],"is_preprint":false},{"year":2026,"finding":"DECR1 loss in trophoblasts disrupts mitochondrial quality control by suppressing mitocytosis, increases PUFA-rich lipid accumulation and lipid peroxidation, causes mitochondrial dysfunction (loss of membrane potential, ROS buildup, ATP depletion), and impairs trophoblast migration and invasion, contributing to preeclampsia-like pathology in vivo.","method":"Genetic/pharmacological DECR1 inhibition in trophoblasts and L-NAME PE mouse model, mitocytosis assays, lipid peroxidation/ROS measurement, mitochondrial functional assays, radical-trapping agent rescue, in vivo hypertension/fetal growth restriction readouts","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined genetic and pharmacological inhibition with multiple mitochondrial functional and lipid readouts, rescue experiments, single lab","pmids":["41862008"],"is_preprint":false},{"year":2026,"finding":"DECR1 is upregulated in calcified vascular smooth muscle cells (VSMCs); DECR1 knockdown alleviated calcification and its overexpression aggravated calcification. Ursolic acid binds DECR1, leading to its degradation and subsequent inhibition of the NF-κB/NLRP3 signaling pathway, reducing downstream inflammatory mediators (cleaved Caspase-1, IL-1β) to suppress vascular calcification.","method":"DECR1 KD/OE in VSMCs and ex vivo arterial rings, in vivo CKD rat and vitamin D3-overloaded mouse models, molecular docking of ursolic acid to DECR1, NF-κB/NLRP3 pathway analysis, immunoblotting","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic gain/loss-of-function with pathway readouts, in vivo models, molecular docking but no in vitro reconstitution of binding; single lab","pmids":["42034130"],"is_preprint":false},{"year":2025,"finding":"Eukaryotic DECR1 can functionally complement an E. coli fadH (prokaryotic 2,4-dienoyl-CoA reductase) mutant for growth on linoleic acid and relief of linoleate-mediated β-oxidation jamming, demonstrating enzymatic activity of DECR1 on PUFA substrates is conserved and sufficient for β-oxidation of complex FA mixtures.","method":"Complementation of E. coli fadH mutant with eukaryotic DECR, growth assays on linoleic acid, in vivo functional rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional complementation in bacterial system, single preprint study, no mutagenesis or structural validation","pmids":["bio_10.1101_2025.01.23.634462"],"is_preprint":true},{"year":2025,"finding":"FTO-mediated m6A demethylation of MZF1 promotes expression of DECR1, thereby enhancing fatty acid β-oxidation during reperfusion and contributing to myocardial ischemia/reperfusion injury through increased oxidative stress.","method":"m6A modification analysis, FTO gain/loss-of-function, MZF1 transcription factor reporter assays, DECR1 expression modulation, cardiomyocyte injury readouts","journal":"Biochemical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway inferred from transcriptional regulation assays, single lab, no direct DECR1 enzymatic assay or protein-level interaction validation","pmids":["41003915"],"is_preprint":false}],"current_model":"DECR1 (2,4-dienoyl-CoA reductase 1) is a mitochondrial auxiliary enzyme of β-oxidation that catalyzes the rate-limiting reduction step required for degradation of polyunsaturated fatty acids (PUFAs); its loss causes accumulation of PUFA-containing phospholipids, lipid peroxidation, and ferroptosis in multiple cell types, while its activity is regulated by androgen receptor signaling (AR negatively regulates DECR1), BMP9, and FTO-MZF1-mediated transcriptional control; DECR1 also directly binds HSL (promoting lipolysis) and PDK4 (activating HDAC3-HADHA deacetylation to amplify FAO), and its mitochondrial localization is dependent on GIPC1-mediated actin transport, with mouse Decr1 additionally forming a high-affinity complex with 2'-5' oligoadenylate immune signaling nucleotides whose functional significance remains undefined."},"narrative":{"mechanistic_narrative":"DECR1 encodes mitochondrial 2,4-dienoyl-CoA reductase, an auxiliary enzyme of β-oxidation that reduces unsaturated enoyl-CoA esters with double bonds at even- and odd-numbered positions [PMID:9403065], and functions as the rate-limiting enzyme for β-oxidation of polyunsaturated fatty acids (PUFAs) [PMID:32686647]. Its catalytic activity on PUFA substrates is conserved enough to complement a prokaryotic 2,4-dienoyl-CoA reductase mutant, restoring growth on linoleic acid [PMID:bio_10.1101_2025.01.23.634462], and is required for its biological effects, since catalytically impaired mutants fail to suppress de novo fatty acid synthesis and tumorigenesis [PMID:17636013]. Across prostate, breast, cardiac, vascular, and placental cell types, loss of DECR1 blocks PUFA catabolism, leading to accumulation of PUFA-containing phospholipids, lipid peroxidation, and ferroptosis, the latter coupled to the SLC7A11/GPX4 axis [PMID:32686647, PMID:39427521, PMID:40467779, PMID:41862008]. Genetic ablation in mice confirms a selective defect in unsaturated—but not saturated—fatty acid breakdown, impairing brown adipose tissue thermogenesis [PMID:31427678]. DECR1 expression is constrained by androgen receptor signaling as a negatively regulated AR target [PMID:32686647] and induced by BMP9 to support cardiac mitochondrial bioenergetics during myocardial infarction [PMID:39315433]. Beyond its enzymatic role, DECR1 engages protein partners that shape lipid metabolism: it directly binds hormone-sensitive lipase to promote its phosphorylation, lipid-droplet translocation, and lipolysis [PMID:34896618], binds PDK4 to drive an HDAC3–HADHA deacetylation cascade amplifying mitochondrial FAO in cardiac injury [PMID:40052435], and its delivery into mitochondria depends on high-affinity binding by the GIPC1 PDZ domain (KD = 16.3 nM) for actin-dependent transport, loss of which depletes mitochondrial DECR1 and promotes ferroptosis [PMID:41787053]. Mouse Decr1 also forms a high-affinity complex with 2'-5' oligoadenylates resolved at 1.4 Å, a species-specific interaction without an identified antiviral or regulatory function [PMID:37676257].","teleology":[{"year":1997,"claim":"Established the molecular identity of human DECR1 as a mitochondrial β-oxidation auxiliary enzyme, providing the gene, locus, and enzymatic assignment needed for all subsequent functional work.","evidence":"Molecular cloning, primer extension, 5' RACE, and FISH chromosomal mapping","pmids":["9403065"],"confidence":"High","gaps":["No structural model of the human enzyme","Substrate range characterized only enzymatically, not in cellular flux"]},{"year":2007,"claim":"Showed that DECR1's catalytic activity, not merely its presence, drives suppression of de novo lipogenesis and tumorigenesis, tying the enzyme to a metabolic-tumor-suppressor role.","evidence":"Active-site mutant expression with in vivo xenograft tumorigenicity and de novo fatty acid synthesis assays in ErbB2/Neu breast cancer cells","pmids":["17636013"],"confidence":"High","gaps":["Mechanism linking PUFA reduction to ErbB2/Neu suppression not defined","Context appears opposite to later pro-tumor roles, unresolved"]},{"year":2019,"claim":"Genetic knockout established in vivo that DECR1 is specifically required for unsaturated, not saturated, fatty acid β-oxidation, with physiological consequences for thermogenesis.","evidence":"Decr-/- mouse with calorimetry, thermography, lipidomics, and lipolysis assays","pmids":["31427678"],"confidence":"High","gaps":["Identity of the suppressive unsaturated metabolites incompletely defined","Link to NE signaling mechanistically indirect"]},{"year":2020,"claim":"Defined DECR1 as the rate-limiting PUFA β-oxidation enzyme whose loss triggers lipid peroxidation and ferroptosis, and placed it under negative AR transcriptional control, framing it as a cancer vulnerability.","evidence":"siRNA knockdown, β-oxidation flux, lipid peroxidation/ROS, xenografts, ex vivo tumors, and AR ChIP in prostate cancer","pmids":["32686647"],"confidence":"High","gaps":["Does not resolve why DECR1 is tumor-suppressive in some contexts and pro-tumor in others","AR-binding site fine mapping not detailed"]},{"year":2021,"claim":"Revealed a non-enzymatic protein-partner role: DECR1 binds and activates HSL to promote lipolysis, expanding its function beyond catalysis.","evidence":"Co-IP, overexpression/silencing, HSL phosphorylation/activity and lipid-droplet translocation imaging in cervical cancer cells","pmids":["34896618"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal or structural validation","Direct binding interface not mapped"]},{"year":2023,"claim":"Determined that mouse Decr1 binds 2'-5' oligoadenylates at atomic resolution, defining species-specific recognition but explicitly finding no antiviral or regulatory function.","evidence":"MS pull-down, biochemical binding, and 1.4 Å co-crystal structure","pmids":["37676257"],"confidence":"High","gaps":["Functional significance of the OA complex undefined","Interaction absent in human DECR1"]},{"year":2024,"claim":"Connected DECR1 to upstream BMP9 signaling and a downstream PDK4–HDAC3–HADHA deacetylation cascade, linking it to cardiac mitochondrial bioenergetics and FAO amplification.","evidence":"AAV expression/knockdown, KO mice, recombinant BMP9, Co-IP (DECR1-PDK4), and epistasis rescue in MI and diabetic cardiomyopathy models","pmids":["39315433","40052435"],"confidence":"Medium","gaps":["Biochemical mechanism of BMP9→DECR1 regulation undefined","DECR1-PDK4 interaction from single-lab Co-IP without structure"]},{"year":2024,"claim":"Placed DECR1 in a ferroptosis-regulatory axis with SLC7A11 and identified it as a degradation target of bufalin, linking its protein stability to ferroptosis outcomes.","evidence":"High-content screening, Co-IP (DECR1-SLC7A11), autophagy/ubiquitination inhibitor assays, and overexpression rescue in breast cancer","pmids":["39427521"],"confidence":"Medium","gaps":["Direct vs. indirect nature of DECR1-SLC7A11 interaction unresolved","Single-lab Co-IP without reciprocal validation"]},{"year":2025,"claim":"Detailed the lipid-metabolic basis of DECR1-loss ferroptosis as a PC/AA axis with ACSL4/PLA2G12A upregulation and GPX4/SLC7A11 loss, and confirmed enzymatic conservation by bacterial complementation.","evidence":"Multi-omics with metabolite validation in breast cancer; E. coli fadH complementation on linoleic acid (preprint)","pmids":["40467779","bio_10.1101_2025.01.23.634462"],"confidence":"Medium","gaps":["Complementation is preprint without mutagenesis","Causal ordering within the PC/AA axis not fully dissected"]},{"year":2026,"claim":"Identified the mechanism of DECR1 mitochondrial delivery through high-affinity GIPC1 PDZ binding and actin transport, explaining how localization controls PUFA-phospholipid clearance and ferroptosis susceptibility.","evidence":"Co-IP/MS, SPR (KD = 16.3 nM), IF colocalization, GIPC1 cardiac KO mouse, and DECR1 rescue","pmids":["41787053"],"confidence":"High","gaps":["Whether GIPC1 transport applies across all tissues unknown","Import machinery downstream of actin delivery not defined"]},{"year":2026,"claim":"Extended the DECR1 ferroptosis/mitochondrial-quality role to additional tissues, implicating it in preeclampsia trophoblast pathology and vascular calcification via NF-κB/NLRP3.","evidence":"Genetic/pharmacological DECR1 modulation in trophoblast PE and VSMC calcification models with in vivo readouts and molecular docking of small-molecule binders","pmids":["41862008","42034130"],"confidence":"Medium","gaps":["Direct DECR1 binding of ursolic acid not reconstituted in vitro","Link between metabolic activity and NF-κB/NLRP3 indirect"]},{"year":2025,"claim":"Proposed an epitranscriptomic regulatory layer in which FTO-MZF1 controls DECR1 expression during cardiac ischemia/reperfusion injury.","evidence":"m6A analysis, FTO gain/loss, MZF1 reporter assays, and cardiomyocyte injury readouts","pmids":["41003915"],"confidence":"Low","gaps":["No direct DECR1 enzymatic or protein-level validation in this axis","MZF1 binding to DECR1 promoter inferred from reporters only"]},{"year":null,"claim":"It remains unresolved why DECR1 acts as a metabolic tumor suppressor in some contexts yet as a pro-survival, pro-disease factor in others, and how its catalytic versus protein-scaffold functions are partitioned.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling tumor-suppressive and pro-tumor/pro-injury roles","Relative contribution of enzymatic vs. binding (HSL, PDK4, SLC7A11) functions undefined","Human structural model and import pathway incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,2,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,6,10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,7,9,11]}],"complexes":[],"partners":["HSL","PDK4","SLC7A11","GIPC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16698","full_name":"2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing], mitochondrial","aliases":["2,4-dienoyl-CoA reductase [NADPH]","4-enoyl-CoA reductase [NADPH]","Short chain dehydrogenase/reductase family 18C member 1"],"length_aa":335,"mass_kda":36.1,"function":"Auxiliary enzyme of beta-oxidation. It participates in the metabolism of unsaturated fatty enoyl-CoA esters having double bonds in both even- and odd-numbered positions in mitochondria. Catalyzes the NADP-dependent reduction of 2,4-dienoyl-CoA to yield trans-3-enoyl-CoA","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q16698/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DECR1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"RELA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DECR1","total_profiled":1310},"omim":[{"mim_id":"616034","title":"2,4-@DIENOYL-CoA REDUCTASE DEFICIENCY; DECRD","url":"https://www.omim.org/entry/616034"},{"mim_id":"604598","title":"OXIDATIVE STRESS-INDUCED GROWTH INHIBITOR FAMILY MEMBER 2; OSGIN2","url":"https://www.omim.org/entry/604598"},{"mim_id":"602667","title":"NIBRIN; NBN","url":"https://www.omim.org/entry/602667"},{"mim_id":"600696","title":"ENOYL-CoA HYDRATASE 1, PEROXISOMAL; ECH1","url":"https://www.omim.org/entry/600696"},{"mim_id":"258500","title":"OPTIC ATROPHY 6; OPA6","url":"https://www.omim.org/entry/258500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":70.1}],"url":"https://www.proteinatlas.org/search/DECR1"},"hgnc":{"alias_symbol":["SDR18C1"],"prev_symbol":["DECR"]},"alphafold":{"accession":"Q16698","domains":[{"cath_id":"3.40.50.720","chopping":"52-313","consensus_level":"high","plddt":96.3026,"start":52,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16698","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16698-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16698-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DECR1","jax_strain_url":"https://www.jax.org/strain/search?query=DECR1"},"sequence":{"accession":"Q16698","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16698.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16698/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16698"}},"corpus_meta":[{"pmid":"32686647","id":"PMC_32686647","title":"Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32686647","citation_count":161,"is_preprint":false},{"pmid":"8485513","id":"PMC_8485513","title":"Cloning of a Chironomus tentans cDNA encoding a protein (cEcRH) homologous to the Drosophila melanogaster ecdysteroid receptor (dEcR).","date":"1993","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8485513","citation_count":79,"is_preprint":false},{"pmid":"17636013","id":"PMC_17636013","title":"Elevated expression of DecR1 impairs ErbB2/Neu-induced mammary tumor development.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17636013","citation_count":48,"is_preprint":false},{"pmid":"27435271","id":"PMC_27435271","title":"Transcription factor DecR (YbaO) controls detoxification of L-cysteine in Escherichia coli.","date":"2016","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27435271","citation_count":47,"is_preprint":false},{"pmid":"9403065","id":"PMC_9403065","title":"Molecular cloning and characterization of the human mitochondrial 2,4-dienoyl-CoA reductase gene (DECR).","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9403065","citation_count":25,"is_preprint":false},{"pmid":"39427521","id":"PMC_39427521","title":"Bufalin induces ferroptosis by modulating the 2,4-dienoyl-CoA reductase (DECR1)-SLC7A11 axis in breast cancer.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39427521","citation_count":22,"is_preprint":false},{"pmid":"34896618","id":"PMC_34896618","title":"DECR1 directly activates HSL to promote lipolysis in cervical cancer cells.","date":"2021","source":"Biochimica et biophysica acta. 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precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40467779","citation_count":9,"is_preprint":false},{"pmid":"37676257","id":"PMC_37676257","title":"RNase L-activating 2'-5' oligoadenylates bind ABCF1, ABCF3 and Decr-1.","date":"2023","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/37676257","citation_count":2,"is_preprint":false},{"pmid":"38634289","id":"PMC_38634289","title":"Engineering of the Lrp/AsnC-type transcriptional regulator DecR as a genetically encoded biosensor for multilevel optimization of L-cysteine biosynthesis pathway in Escherichia coli.","date":"2024","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/38634289","citation_count":2,"is_preprint":false},{"pmid":"40613293","id":"PMC_40613293","title":"Atorvastatin Calcium Enhances Ferroptosis in Breast Cancer Cells Through Mechanisms Involving DECR1.","date":"2025","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/40613293","citation_count":1,"is_preprint":false},{"pmid":"38768919","id":"PMC_38768919","title":"Exploring the molecular mechanisms of Lrp/AsnC-type transcription regulator DecR, an L-cysteine-responsive feast/famine regulatory protein.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38768919","citation_count":1,"is_preprint":false},{"pmid":"41003915","id":"PMC_41003915","title":"FTO-Mediated m6A Demethylation of MZF1 Regulates DECR1 to Promote Fatty Acid Oxidation and Exacerbate Myocardial Ischemia/Reperfusion Injury : FTO-Mediated m6A Demethylation of MZF1 Enhances Fatty Acid Oxidation and Aggravates Myocardial I/R Injury.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41003915","citation_count":1,"is_preprint":false},{"pmid":"41787053","id":"PMC_41787053","title":"GIPC1 governed ferroptosis by regulating DECR1-modulating lipid homeostasis during dilated cardiomyopathy (DCM).","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41787053","citation_count":0,"is_preprint":false},{"pmid":"41862008","id":"PMC_41862008","title":"DECR1 deficiency activates a lipid peroxidation-mitocytosis-mitochondrial dysfunction axis in trophoblasts to promote preeclampsia.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41862008","citation_count":0,"is_preprint":false},{"pmid":"42034130","id":"PMC_42034130","title":"DECR1 degradation by ursolic acid alleviates vascular calcification through inhibition of NF-κB/NLRP3 signaling pathway.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42034130","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.23.634462","title":"The essential role of 2,4-dienoyl-CoA reductase for degradation of complex fatty acid mixtures","date":"2025-01-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.23.634462","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14113,"output_tokens":4237,"usd":0.052947,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12261,"output_tokens":4181,"usd":0.082915,"stage2_stop_reason":"end_turn"},"total_usd":0.135862,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Human DECR1 encodes the 120-kDa isoform of mitochondrial 2,4-dienoyl-CoA reductase (EC 1.3.1.34), an auxiliary enzyme of β-oxidation that participates in the metabolism of unsaturated fatty enoyl-CoA esters having double bonds in both even- and odd-numbered positions. The gene comprises 10 exons, lacks a TATA box, and was mapped to chromosomal band 8q21.3 by FISH.\",\n      \"method\": \"Molecular cloning, primer extension, 5' RACE-PCR, FISH on metaphase chromosomes\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct molecular cloning, enzymatic characterization (EC number assignment), and chromosomal localization by FISH in a single focused study\",\n      \"pmids\": [\"9403065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ectopic expression of catalytically impaired DecR1 mutants (vs. wild-type) in ErbB2/Neu-transformed breast cancer cells restored Neu expression and increased mammary tumorigenesis in vivo, demonstrating that DECR1's enzymatic activity is required for its tumor-suppressive effects, including reduction of de novo fatty acid synthesis rates and suppression of ErbB2/Neu expression.\",\n      \"method\": \"Catalytic mutant expression, in vivo xenograft tumorigenic assays, de novo fatty acid synthesis measurements, proliferation index assessment\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — active-site mutagenesis combined with in vivo functional readouts and biochemical de novo lipid synthesis assay in a single study\",\n      \"pmids\": [\"17636013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DECR1 is the rate-limiting enzyme for β-oxidation of polyunsaturated fatty acids (PUFAs) in prostate cancer cells. DECR1 knockdown selectively inhibited PUFA β-oxidation, caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. DECR1 is a negatively-regulated androgen receptor (AR) target gene.\",\n      \"method\": \"siRNA knockdown, β-oxidation flux assays, lipid peroxidation/ROS measurement, mouse xenograft models, ex vivo clinical tumor culture, androgen receptor ChIP/regulation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (flux assay, lipid peroxidation, in vivo models, AR regulation), replicated across multiple cell lines and clinical samples\",\n      \"pmids\": [\"32686647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Decr-deficient (Decr-/-) mice display intact β-oxidation of saturated fatty acids but blunted breakdown of unsaturated fatty acids, leading to failure of brown adipose tissue (BAT) thermogenesis upon cold challenge due to accumulation of unsaturated long-chain fatty acids/metabolites that suppress downstream norepinephrine (NE) signaling, despite functional NE signaling and inappropriate thermogenic gene expression.\",\n      \"method\": \"Decr knockout mouse model, indirect calorimetry, thermography, MRI, electron microscopy, mass spectrometry, biochemical lipolysis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse with multiple orthogonal phenotypic and biochemical readouts in a single focused study\",\n      \"pmids\": [\"31427678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DECR1 directly interacts with hormone-sensitive lipase (HSL), and this interaction increases HSL phosphorylation and activity, facilitating translocation of HSL to lipid droplets, thereby promoting lipolysis and release of free fatty acids to support cervical cancer cell migration and growth.\",\n      \"method\": \"Co-immunoprecipitation, DECR1 overexpression/silencing, TAG content measurement, HSL phosphorylation and activity assays, lipid droplet translocation imaging\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and functional assays in a single lab, multiple readouts but no structural or in vitro reconstitution\",\n      \"pmids\": [\"34896618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mouse (but not human or Drosophila) Decr1 forms a high-affinity complex with 2'-5' oligoadenylates (OAs), innate immune signaling nucleotides. A 1.4 Å co-crystal structure of mouse Decr1 bound to 2'-5' OA revealed the structural basis of high-affinity recognition and the mechanism of species specificity. No profound antiviral function of Decr1 or 2'-5' OA-dependent regulation through Decr1 was identified.\",\n      \"method\": \"Mass spectrometry pull-down, biochemical binding characterization, 1.4 Å co-crystal structure\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure with biochemical binding validation; negative functional finding explicitly noted\",\n      \"pmids\": [\"37676257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BMP9 increases the expression of mitochondrial DECR1 in the heart, promoting cardiac mitochondrial bioenergetics and mitigating myocardial infarction-induced cardiomyocyte injury. DECR1 deficiency exacerbates MI-induced cardiac damage, and this adverse effect is restored by AAV-mediated DECR1 re-expression. DECR1 deletion abrogates the cardioprotective effect of BMP9.\",\n      \"method\": \"AAV-mediated gene expression/knockdown in mouse MI models, cardiac function assessment (echocardiography), DECR1 KO mice, recombinant BMP9 treatment, immunoblot\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic rescue experiments with functional cardiac readouts, single lab, no biochemical mechanism of BMP9→DECR1 regulation defined\",\n      \"pmids\": [\"39315433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Bufalin promotes degradation of DECR1 via autophagy and ubiquitination pathways. DECR1 interacts with SLC7A11; inhibition of SLC7A11 decreases DECR1 expression. DECR1 overexpression reverses bufalin-induced ferroptosis (accumulation of MDA, ROS, Fe2+; downregulation of SLC7A11, GPX4), establishing a DECR1-SLC7A11 axis in breast cancer ferroptosis regulation.\",\n      \"method\": \"High-content screening, molecular docking, Co-immunoprecipitation (DECR1-SLC7A11 interaction), autophagy/ubiquitination inhibitor assays, DECR1 overexpression rescue, in vivo tumor models\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction, multiple functional assays with rescue, single lab; structural mechanism not established\",\n      \"pmids\": [\"39427521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DECR1 interacts with and upregulates pyruvate dehydrogenase kinase 4 (PDK4) in injured cardiomyocytes. PDK4 acts as a kinase that induces phosphorylation and mitochondrial translocation of HDAC3. In mitochondria, HDAC3 mediates deacetylation of HADHA (dehydrogenase trifunctional multienzyme complex α subunit), contributing to excessive mitochondrial FAO and cardiac injury in diabetic cardiomyopathy.\",\n      \"method\": \"RNA sequencing, gain/loss-of-function (cardiomyocyte-specific KD/OE), Co-immunoprecipitation (DECR1-PDK4), PDK4 overexpression epistasis rescue experiments, neonatal rat cardiomyocyte HG/HP model, T2D mouse model\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for DECR1-PDK4, epistasis via PDK4 OE rescue, multiple functional readouts, single lab\",\n      \"pmids\": [\"40052435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DECR1 knockdown in breast cancer cells inhibits production of arachidonic acid (AA) with phosphatidylcholine (PC) accumulation, elevates PLA2G12A expression, increases ACSL4, and decreases GPX4/SLC7A11, inducing ferroptosis via a PC/AA metabolic axis.\",\n      \"method\": \"siRNA knockdown, multi-omics (transcriptomic + lipidomic), metabolite detection, western blotting, virtual screening for inhibitor Erigoster B\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics with metabolite validation and functional ferroptosis readouts, single lab\",\n      \"pmids\": [\"40467779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GIPC1 directly binds DECR1 via its PDZ domain (KD = 16.3 nM by SPR) and facilitates actin-dependent transport of DECR1 into mitochondria. GIPC1 deficiency reduces DECR1 mitochondrial localization, increases PUFA-containing phospholipids, and promotes ferroptosis; DECR1 overexpression rescues GIPC1 ablation-induced ferroptosis.\",\n      \"method\": \"Co-IP/MS, molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation, immunofluorescence colocalization, GIPC1 cardiac-specific KO mouse, proteomic + lipidomic analysis, DECR1 OE rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPR quantitative binding (KD), Co-IP/MS, IF localization, in vivo KO with rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41787053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DECR1 loss in trophoblasts disrupts mitochondrial quality control by suppressing mitocytosis, increases PUFA-rich lipid accumulation and lipid peroxidation, causes mitochondrial dysfunction (loss of membrane potential, ROS buildup, ATP depletion), and impairs trophoblast migration and invasion, contributing to preeclampsia-like pathology in vivo.\",\n      \"method\": \"Genetic/pharmacological DECR1 inhibition in trophoblasts and L-NAME PE mouse model, mitocytosis assays, lipid peroxidation/ROS measurement, mitochondrial functional assays, radical-trapping agent rescue, in vivo hypertension/fetal growth restriction readouts\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined genetic and pharmacological inhibition with multiple mitochondrial functional and lipid readouts, rescue experiments, single lab\",\n      \"pmids\": [\"41862008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DECR1 is upregulated in calcified vascular smooth muscle cells (VSMCs); DECR1 knockdown alleviated calcification and its overexpression aggravated calcification. Ursolic acid binds DECR1, leading to its degradation and subsequent inhibition of the NF-κB/NLRP3 signaling pathway, reducing downstream inflammatory mediators (cleaved Caspase-1, IL-1β) to suppress vascular calcification.\",\n      \"method\": \"DECR1 KD/OE in VSMCs and ex vivo arterial rings, in vivo CKD rat and vitamin D3-overloaded mouse models, molecular docking of ursolic acid to DECR1, NF-κB/NLRP3 pathway analysis, immunoblotting\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic gain/loss-of-function with pathway readouts, in vivo models, molecular docking but no in vitro reconstitution of binding; single lab\",\n      \"pmids\": [\"42034130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Eukaryotic DECR1 can functionally complement an E. coli fadH (prokaryotic 2,4-dienoyl-CoA reductase) mutant for growth on linoleic acid and relief of linoleate-mediated β-oxidation jamming, demonstrating enzymatic activity of DECR1 on PUFA substrates is conserved and sufficient for β-oxidation of complex FA mixtures.\",\n      \"method\": \"Complementation of E. coli fadH mutant with eukaryotic DECR, growth assays on linoleic acid, in vivo functional rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional complementation in bacterial system, single preprint study, no mutagenesis or structural validation\",\n      \"pmids\": [\"bio_10.1101_2025.01.23.634462\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FTO-mediated m6A demethylation of MZF1 promotes expression of DECR1, thereby enhancing fatty acid β-oxidation during reperfusion and contributing to myocardial ischemia/reperfusion injury through increased oxidative stress.\",\n      \"method\": \"m6A modification analysis, FTO gain/loss-of-function, MZF1 transcription factor reporter assays, DECR1 expression modulation, cardiomyocyte injury readouts\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway inferred from transcriptional regulation assays, single lab, no direct DECR1 enzymatic assay or protein-level interaction validation\",\n      \"pmids\": [\"41003915\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DECR1 (2,4-dienoyl-CoA reductase 1) is a mitochondrial auxiliary enzyme of β-oxidation that catalyzes the rate-limiting reduction step required for degradation of polyunsaturated fatty acids (PUFAs); its loss causes accumulation of PUFA-containing phospholipids, lipid peroxidation, and ferroptosis in multiple cell types, while its activity is regulated by androgen receptor signaling (AR negatively regulates DECR1), BMP9, and FTO-MZF1-mediated transcriptional control; DECR1 also directly binds HSL (promoting lipolysis) and PDK4 (activating HDAC3-HADHA deacetylation to amplify FAO), and its mitochondrial localization is dependent on GIPC1-mediated actin transport, with mouse Decr1 additionally forming a high-affinity complex with 2'-5' oligoadenylate immune signaling nucleotides whose functional significance remains undefined.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DECR1 encodes mitochondrial 2,4-dienoyl-CoA reductase, an auxiliary enzyme of β-oxidation that reduces unsaturated enoyl-CoA esters with double bonds at even- and odd-numbered positions [#0], and functions as the rate-limiting enzyme for β-oxidation of polyunsaturated fatty acids (PUFAs) [#2]. Its catalytic activity on PUFA substrates is conserved enough to complement a prokaryotic 2,4-dienoyl-CoA reductase mutant, restoring growth on linoleic acid [#13], and is required for its biological effects, since catalytically impaired mutants fail to suppress de novo fatty acid synthesis and tumorigenesis [#1]. Across prostate, breast, cardiac, vascular, and placental cell types, loss of DECR1 blocks PUFA catabolism, leading to accumulation of PUFA-containing phospholipids, lipid peroxidation, and ferroptosis, the latter coupled to the SLC7A11/GPX4 axis [#2, #7, #9, #11]. Genetic ablation in mice confirms a selective defect in unsaturated—but not saturated—fatty acid breakdown, impairing brown adipose tissue thermogenesis [#3]. DECR1 expression is constrained by androgen receptor signaling as a negatively regulated AR target [#2] and induced by BMP9 to support cardiac mitochondrial bioenergetics during myocardial infarction [#6]. Beyond its enzymatic role, DECR1 engages protein partners that shape lipid metabolism: it directly binds hormone-sensitive lipase to promote its phosphorylation, lipid-droplet translocation, and lipolysis [#4], binds PDK4 to drive an HDAC3–HADHA deacetylation cascade amplifying mitochondrial FAO in cardiac injury [#8], and its delivery into mitochondria depends on high-affinity binding by the GIPC1 PDZ domain (KD = 16.3 nM) for actin-dependent transport, loss of which depletes mitochondrial DECR1 and promotes ferroptosis [#10]. Mouse Decr1 also forms a high-affinity complex with 2'-5' oligoadenylates resolved at 1.4 Å, a species-specific interaction without an identified antiviral or regulatory function [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity of human DECR1 as a mitochondrial β-oxidation auxiliary enzyme, providing the gene, locus, and enzymatic assignment needed for all subsequent functional work.\",\n      \"evidence\": \"Molecular cloning, primer extension, 5' RACE, and FISH chromosomal mapping\",\n      \"pmids\": [\"9403065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the human enzyme\", \"Substrate range characterized only enzymatically, not in cellular flux\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that DECR1's catalytic activity, not merely its presence, drives suppression of de novo lipogenesis and tumorigenesis, tying the enzyme to a metabolic-tumor-suppressor role.\",\n      \"evidence\": \"Active-site mutant expression with in vivo xenograft tumorigenicity and de novo fatty acid synthesis assays in ErbB2/Neu breast cancer cells\",\n      \"pmids\": [\"17636013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PUFA reduction to ErbB2/Neu suppression not defined\", \"Context appears opposite to later pro-tumor roles, unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic knockout established in vivo that DECR1 is specifically required for unsaturated, not saturated, fatty acid β-oxidation, with physiological consequences for thermogenesis.\",\n      \"evidence\": \"Decr-/- mouse with calorimetry, thermography, lipidomics, and lipolysis assays\",\n      \"pmids\": [\"31427678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the suppressive unsaturated metabolites incompletely defined\", \"Link to NE signaling mechanistically indirect\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined DECR1 as the rate-limiting PUFA β-oxidation enzyme whose loss triggers lipid peroxidation and ferroptosis, and placed it under negative AR transcriptional control, framing it as a cancer vulnerability.\",\n      \"evidence\": \"siRNA knockdown, β-oxidation flux, lipid peroxidation/ROS, xenografts, ex vivo tumors, and AR ChIP in prostate cancer\",\n      \"pmids\": [\"32686647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve why DECR1 is tumor-suppressive in some contexts and pro-tumor in others\", \"AR-binding site fine mapping not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a non-enzymatic protein-partner role: DECR1 binds and activates HSL to promote lipolysis, expanding its function beyond catalysis.\",\n      \"evidence\": \"Co-IP, overexpression/silencing, HSL phosphorylation/activity and lipid-droplet translocation imaging in cervical cancer cells\",\n      \"pmids\": [\"34896618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal or structural validation\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Determined that mouse Decr1 binds 2'-5' oligoadenylates at atomic resolution, defining species-specific recognition but explicitly finding no antiviral or regulatory function.\",\n      \"evidence\": \"MS pull-down, biochemical binding, and 1.4 Å co-crystal structure\",\n      \"pmids\": [\"37676257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of the OA complex undefined\", \"Interaction absent in human DECR1\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected DECR1 to upstream BMP9 signaling and a downstream PDK4–HDAC3–HADHA deacetylation cascade, linking it to cardiac mitochondrial bioenergetics and FAO amplification.\",\n      \"evidence\": \"AAV expression/knockdown, KO mice, recombinant BMP9, Co-IP (DECR1-PDK4), and epistasis rescue in MI and diabetic cardiomyopathy models\",\n      \"pmids\": [\"39315433\", \"40052435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical mechanism of BMP9→DECR1 regulation undefined\", \"DECR1-PDK4 interaction from single-lab Co-IP without structure\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed DECR1 in a ferroptosis-regulatory axis with SLC7A11 and identified it as a degradation target of bufalin, linking its protein stability to ferroptosis outcomes.\",\n      \"evidence\": \"High-content screening, Co-IP (DECR1-SLC7A11), autophagy/ubiquitination inhibitor assays, and overexpression rescue in breast cancer\",\n      \"pmids\": [\"39427521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of DECR1-SLC7A11 interaction unresolved\", \"Single-lab Co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detailed the lipid-metabolic basis of DECR1-loss ferroptosis as a PC/AA axis with ACSL4/PLA2G12A upregulation and GPX4/SLC7A11 loss, and confirmed enzymatic conservation by bacterial complementation.\",\n      \"evidence\": \"Multi-omics with metabolite validation in breast cancer; E. coli fadH complementation on linoleic acid (preprint)\",\n      \"pmids\": [\"40467779\", \"bio_10.1101_2025.01.23.634462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Complementation is preprint without mutagenesis\", \"Causal ordering within the PC/AA axis not fully dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified the mechanism of DECR1 mitochondrial delivery through high-affinity GIPC1 PDZ binding and actin transport, explaining how localization controls PUFA-phospholipid clearance and ferroptosis susceptibility.\",\n      \"evidence\": \"Co-IP/MS, SPR (KD = 16.3 nM), IF colocalization, GIPC1 cardiac KO mouse, and DECR1 rescue\",\n      \"pmids\": [\"41787053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GIPC1 transport applies across all tissues unknown\", \"Import machinery downstream of actin delivery not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the DECR1 ferroptosis/mitochondrial-quality role to additional tissues, implicating it in preeclampsia trophoblast pathology and vascular calcification via NF-κB/NLRP3.\",\n      \"evidence\": \"Genetic/pharmacological DECR1 modulation in trophoblast PE and VSMC calcification models with in vivo readouts and molecular docking of small-molecule binders\",\n      \"pmids\": [\"41862008\", \"42034130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DECR1 binding of ursolic acid not reconstituted in vitro\", \"Link between metabolic activity and NF-κB/NLRP3 indirect\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed an epitranscriptomic regulatory layer in which FTO-MZF1 controls DECR1 expression during cardiac ischemia/reperfusion injury.\",\n      \"evidence\": \"m6A analysis, FTO gain/loss, MZF1 reporter assays, and cardiomyocyte injury readouts\",\n      \"pmids\": [\"41003915\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct DECR1 enzymatic or protein-level validation in this axis\", \"MZF1 binding to DECR1 promoter inferred from reporters only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved why DECR1 acts as a metabolic tumor suppressor in some contexts yet as a pro-survival, pro-disease factor in others, and how its catalytic versus protein-scaffold functions are partitioned.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling tumor-suppressive and pro-tumor/pro-injury roles\", \"Relative contribution of enzymatic vs. binding (HSL, PDK4, SLC7A11) functions undefined\", \"Human structural model and import pathway incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 7, 9, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSL\", \"PDK4\", \"SLC7A11\", \"GIPC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}