{"gene":"DHRS3","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2013,"finding":"DHRS3 functions as a retinaldehyde reductase essential for preventing excess retinoic acid formation during embryonic development. Dhrs3-knockout mice show a 40% increase in ATRA levels, 60% decrease in retinol, and 55% decrease in retinyl esters, along with compensatory changes in ATRA synthetic/catabolic genes (Cyp26a1 upregulated 120%). Knockout embryos die late in gestation with cardiac outflow tract, septal, skeletal, and palate defects.","method":"Dhrs3-deficient mouse model with quantitative retinoid metabolite measurements and gene expression analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with specific quantitative phenotypic readouts, multiple orthogonal methods (metabolite measurement, gene expression), independently consistent with other studies","pmids":["24005908"],"is_preprint":false},{"year":2013,"finding":"Dhrs3 (Xenopus) attenuates retinoic acid signaling by reducing all-trans-retinal levels. Overexpression of Dhrs3 counteracted the effects of Aldh1a2 or Rdh10 overexpression on RA signaling. Morpholino knockdown of Dhrs3 caused shortened anteroposterior axis, reduced head structure, and defective convergent extension movement, phenocopying excess RA treatment.","method":"Xenopus gain-of-function (overexpression) and loss-of-function (antisense morpholino knockdown) with phenotypic analysis and animal cap assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss of function in Xenopus with defined pathway placement (antagonizing Aldh1a2/Rdh10), multiple phenotypic readouts","pmids":["24045938"],"is_preprint":false},{"year":2002,"finding":"retSDR1/DHRS3 (short-chain dehydrogenase/reductase) promotes accumulation of retinyl esters when overexpressed in SK-N-AS neuroblastoma cells exposed to physiological retinol concentrations, indicating it generates storage forms of retinol from retinal. Expression is strongly induced by retinoic acid in neuroblastoma cell lines.","method":"Exogenous overexpression of retSDR1 in SK-N-AS cells with retinyl ester measurement; retinoic acid treatment with expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression assay with functional metabolite readout, single lab, consistent with biochemical role","pmids":["11861404"],"is_preprint":false},{"year":2011,"finding":"DHRS3 is an endoplasmic reticulum (ER) protein targeted via an N-terminal ER targeting signal, and it localizes to focal points of lipid droplet budding and to the phospholipid monolayer of ER-derived lipid droplets. p53 promotes lipid droplet accumulation consistent with DHRS3 enrichment at these sites. DHRS3 is identified as a p53 target gene.","method":"Subcellular fractionation, fluorescence/confocal microscopy for ER and lipid droplet co-localization, p53 microarray target identification, p53 overexpression/activation experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization by imaging/fractionation tied to functional consequence (lipid droplet accumulation), single lab, p53 target validated by microarray and functional assay","pmids":["21659514"],"is_preprint":false},{"year":2010,"finding":"DHRS3/retSDR1 transcription is activated by p53 and TAp63γ through two separate response elements in the retSDR1 promoter. Both proteins bind the promoter in vitro and in vivo (ChIP). Tumor-derived p53 mutants and EEC syndrome-specific TAp63γ mutants fail to activate retSDR1 transcription. DNA damage leads to recruitment of p53 and p63 to the retSDR1 promoter.","method":"Promoter reporter assays, in vitro binding assays, chromatin immunoprecipitation (ChIP), mutagenesis of response elements, DNA damage induction","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding, ChIP in vivo, mutagenesis, multiple orthogonal methods in a single study","pmids":["20543567"],"is_preprint":false},{"year":2012,"finding":"DHRS3 mRNA is strongly induced (30–40 fold) by retinoic acid via RAR-α-selective signaling in THP-1 monocytes, and is suppressed >90% by LPS in rat liver. DHRS3 is a microsomal protein producing two major isoforms (~30 and ~35 kDa) detected by in vitro transcription-translation. DHRS3 mRNA is most abundant in rat adrenal gland, liver, and ovary.","method":"Microarray and RT-PCR for expression; in vitro transcription-translation; selective retinoid agonist treatment (Am580, RAR-α selective); rat tissue expression and LPS/RA treatment in vivo","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro transcription-translation plus pharmacological dissection of RAR subtype, single lab","pmids":["22790594"],"is_preprint":false},{"year":2014,"finding":"Recombinant human DHRS3 is a microsomal, integral-membrane protein with C-terminus oriented toward the cytosol and preferring NADPH as cofactor. In addition to all-trans-retinal, DHRS3 metabolizes endogenous substrates including androstenedione, estrone, and DL-glyceraldehyde, and xenobiotics NNK and acetohexamide. The enzyme was purified and reconstituted in vitro for the first time.","method":"Recombinant protein expression, membrane topology determination, cofactor preference assays (NADPH vs. NADH), in vitro enzymatic assays with multiple substrates, purification and reconstitution","journal":"Chemico-biological interactions","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted purified enzyme with multiple substrate assays and topology determination, single lab but multiple orthogonal biochemical methods","pmids":["25451588"],"is_preprint":false},{"year":2024,"finding":"Mouse Dhrs3 expression is directly regulated by the RAR/RXR complex through cis-regulatory elements in a negative feedback mechanism responsive to vitamin A/retinoic acid status, ensuring retinoic acid homeostasis.","method":"Reporter assays with cis-regulatory element mapping, vitamin A status manipulation in mice, RAR/RXR complex binding assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cis-element mapping with functional assays, single lab","pmids":["39420244"],"is_preprint":false},{"year":2025,"finding":"Human DHRS3 missense variant p.(Val171Met) reduces retinaldehyde-to-retinol reduction capacity in transfected cells, yielding reduced retinol and elevated RA. Additional missense variants p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln) reduce DHRS3 catalytic activity in vitro and/or in vivo. Patients homozygous for the Val171Met variant have reduced plasma retinol and elevated RA. Biallelic loss of DHRS3 causes a congenital syndrome with coronal craniosynostosis, congenital heart disease, and scoliosis.","method":"Cell transfection with mutant DHRS3 constructs and retinoid metabolite quantification; plasma retinoid measurements in patients; in vitro enzymatic activity assays for mutants","journal":"Genetics in medicine open","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro mutagenesis with functional enzymatic readout, confirmed with patient plasma metabolites and multiple variant alleles across independent families","pmids":["40519748"],"is_preprint":false},{"year":2018,"finding":"miR-223 directly targets DHRS3 mRNA (confirmed by dual luciferase assay), suppressing DHRS3 expression and inhibiting osteoblast differentiation of human bone marrow-derived mesenchymal stem cells. Overexpression of DHRS3 promotes osteogenic differentiation (increased ALP activity, matrix calcification, Runx2/OPN/OCN expression), and rescue by DHRS3 cDNA reverses miR-223 inhibition.","method":"Dual luciferase reporter assay, miR-223 mimic/inhibitor transfection, DHRS3 overexpression, ALP staining, ARS staining, western blotting for differentiation markers","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct target validation by luciferase assay, gain/loss of function, rescue experiment; single lab","pmids":["29794437"],"is_preprint":false},{"year":2024,"finding":"DHRS3 localizes to lipid droplets in melanoma cells (confirmed by proteomics of the lipid droplet envelope). Increased DHRS3 expression drives MITFHI/melanocytic cells toward a more undifferentiated/invasive state via retinoic acid-mediated regulation of melanocytic genes.","method":"Proteomic analysis of lipid droplet envelope fractions from melanoma cells, DHRS3 overexpression with cell state and gene expression analysis","journal":"Pigment cell & melanoma research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomic fractionation confirming lipid droplet localization, gain-of-function with defined downstream pathway (RA signaling), single lab","pmids":["39479752"],"is_preprint":false},{"year":2026,"finding":"DHRS3 protein is stabilized post-transcriptionally by YTHDF2, which recognizes an m6A-modified site in the DHRS3 3' UTR. After irradiation, DHRS3 localizes at ER-lipid droplet regions juxtaposed to mitochondria, facilitated by LRAT. DHRS3 depletion elevates ROS, disrupts NADP+/NADPH ratios, and abrogates radioprotective effects of YTHDF2. LRAT loss disperses ER-LD interfaces and mislocalizes DHRS3, impairing retinoid and NADPH buffering.","method":"MeRIP-seq, MeRIP-qPCR, reporter assays for m6A site validation; DHRS3 knockdown/YTHDF2 overexpression with ROS and clonogenic survival assays; spatial imaging of organelle contacts; LRAT perturbation; enforced mitochondrial targeting of DHRS3","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeRIP-seq, reporter, imaging, metabolic assays), single lab, 2026 publication","pmids":["41579973"],"is_preprint":false},{"year":2026,"finding":"DHRS3 physically interacts with Nrf2 (shown by co-immunoprecipitation and GST pull-down). This protein-protein interaction can be disrupted by compound Cpd.51. DHRS3 expression is suppressed as a downstream target of Nrf2 transcriptional activity (Nrf2 activation reduces DHRS3).","method":"Co-immunoprecipitation, GST pull-down, surface plasmon resonance, cellular thermal shift assay, chromatin immunoprecipitation, RNA sequencing","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods to confirm interaction (Co-IP, pulldown, SPR, CETSA), single lab","pmids":["41993611"],"is_preprint":false}],"current_model":"DHRS3 is a microsomal, integral-membrane short-chain dehydrogenase/reductase that uses NADPH to reduce all-trans-retinal to retinol (and also metabolizes androstenedione, estrone, and xenobiotics), thereby limiting excessive retinoic acid synthesis; its expression is transcriptionally induced by retinoic acid through RAR/RXR cis-elements (negative feedback), activated by p53 and TAp63γ via promoter response elements, and post-transcriptionally stabilized by YTHDF2-mediated m6A recognition; it localizes to the ER and lipid droplets (facilitated by LRAT at ER-LD-mitochondria interfaces) where it buffers NADPH/redox status, and loss of DHRS3 in mice or humans causes excess RA with embryonic/congenital defects including cardiac, skeletal, and craniofacial malformations."},"narrative":{"mechanistic_narrative":"DHRS3 is a microsomal, integral-membrane short-chain dehydrogenase/reductase that uses NADPH to reduce all-trans-retinal to retinol, thereby constraining the synthesis of retinoic acid and serving as a central buffer of retinoid homeostasis during development [PMID:24005908, PMID:25451588]. The purified enzyme prefers NADPH over NADH and, beyond retinaldehyde, also reduces androstenedione, estrone, and xenobiotic substrates [PMID:25451588]. Functionally, DHRS3 acts in opposition to the RA-generating machinery (Aldh1a2/Rdh10): its knockdown phenocopies excess RA while its overexpression counteracts retinal-driven RA signaling [PMID:24045938], and in cell models it promotes accumulation of retinyl ester storage forms of retinol [PMID:11861404]. This activity is embedded in negative-feedback control of RA: DHRS3 transcription is directly induced by retinoic acid through RAR/RXR cis-regulatory elements [PMID:39420244], and it is additionally a transcriptional target of p53 and TAp63γ acting through distinct promoter response elements following DNA damage [PMID:20543567, PMID:21659514]. DHRS3 localizes to the ER and to lipid droplets, including ER–lipid-droplet interfaces juxtaposed to mitochondria where it supports NADPH/redox buffering and limits ROS [PMID:21659514, PMID:41579973]. Loss-of-function in mice produces excess ATRA with cardiac outflow tract, septal, skeletal, and palate defects [PMID:24005908], and biallelic catalytically impairing variants in humans cause a congenital syndrome of coronal craniosynostosis, congenital heart disease, and scoliosis with reduced plasma retinol and elevated RA [PMID:40519748].","teleology":[{"year":2002,"claim":"Established that DHRS3/retSDR1 acts on retinoid metabolism by generating retinol storage forms and that its expression is responsive to retinoic acid, first linking the enzyme to vitamin A handling.","evidence":"Overexpression of retSDR1 in SK-N-AS neuroblastoma cells with retinyl ester measurement and RA-induction expression analysis","pmids":["11861404"],"confidence":"Medium","gaps":["Overexpression-only, no direct enzymatic kinetics","Direction of reaction (retinal→retinol vs storage) inferred from metabolite pools","No in vivo validation"]},{"year":2010,"claim":"Identified the transcriptional control of DHRS3 by tumor-suppressor transcription factors, placing the gene downstream of p53/TAp63γ stress and developmental signaling.","evidence":"Promoter reporter assays, in vitro binding, ChIP, response-element mutagenesis, and DNA damage induction","pmids":["20543567"],"confidence":"High","gaps":["Does not establish the biochemical function of the DHRS3 protein itself","Link between p53/p63 induction and retinoid outcome not measured"]},{"year":2011,"claim":"Defined DHRS3 subcellular localization to the ER and lipid droplets via an N-terminal targeting signal, connecting its activity to lipid-storage organelles and confirming it as a p53 target.","evidence":"Subcellular fractionation, confocal co-localization, p53 microarray target identification and activation experiments","pmids":["21659514"],"confidence":"Medium","gaps":["Mechanistic role of LD localization in catalysis not resolved","Single lab","Topology not yet determined"]},{"year":2012,"claim":"Showed DHRS3 induction is RAR-α-selective and that it is a microsomal protein, refining the receptor subtype driving its feedback regulation.","evidence":"Microarray/RT-PCR, in vitro transcription-translation, RAR-α-selective agonist (Am580), and rat tissue/LPS/RA treatments in vivo","pmids":["22790594"],"confidence":"Medium","gaps":["Two isoforms detected but functional difference unknown","Cis-elements not yet mapped"]},{"year":2013,"claim":"Demonstrated in vivo that DHRS3 is a retinaldehyde reductase essential for limiting embryonic ATRA, resolving the physiological consequence of its enzymatic activity.","evidence":"Dhrs3-knockout mouse with quantitative retinoid metabolite measurement and RA gene-expression analysis; reciprocal Xenopus gain/loss-of-function antagonizing Aldh1a2/Rdh10","pmids":["24005908","24045938"],"confidence":"High","gaps":["Direct in vitro enzymatic reconstitution not yet performed","Cofactor preference inferred not measured"]},{"year":2014,"claim":"Biochemically defined DHRS3 as an integral-membrane, NADPH-preferring reductase with a broad substrate range, providing the first reconstitution of purified enzyme.","evidence":"Recombinant expression, membrane topology determination, NADPH/NADH cofactor assays, multi-substrate enzymatic assays, purification and reconstitution","pmids":["25451588"],"confidence":"High","gaps":["No structural model","Relative physiological importance of non-retinoid substrates unknown"]},{"year":2018,"claim":"Extended DHRS3 regulation to the post-transcriptional level and to a new cellular outcome, showing miR-223 represses DHRS3 to control osteoblast differentiation.","evidence":"Dual-luciferase target validation, miR-223 mimic/inhibitor, DHRS3 overexpression and rescue, differentiation marker assays in human MSCs","pmids":["29794437"],"confidence":"Medium","gaps":["Whether retinoid metabolism mediates the osteogenic effect not established","Single lab"]},{"year":2024,"claim":"Mapped the direct RAR/RXR cis-regulatory feedback loop and added a tumor-context role for DHRS3 in driving melanoma cell-state plasticity.","evidence":"Reporter assays with cis-element mapping and vitamin-A manipulation in mice; lipid-droplet envelope proteomics and overexpression in melanoma cells","pmids":["39420244","39479752"],"confidence":"Medium","gaps":["RAR/RXR element mapping in mouse; human conservation not addressed","Melanoma role from gain-of-function only"]},{"year":2025,"claim":"Established DHRS3 as a Mendelian disease gene, showing biallelic catalytically impairing variants cause a congenital craniofacial/cardiac/skeletal syndrome through excess RA.","evidence":"Cell transfection of mutant constructs with retinoid metabolite quantification, in vitro activity assays for multiple alleles, and patient plasma retinoid measurements","pmids":["40519748"],"confidence":"High","gaps":["Genotype–phenotype correlation across variants incomplete","No structural rationale for specific missense effects"]},{"year":2026,"claim":"Connected DHRS3 to redox buffering and organelle contact sites, showing m6A/YTHDF2 stabilization and LRAT-dependent ER-LD-mitochondria positioning underlie its radioprotective NADPH/ROS function, and identified an Nrf2 physical and transcriptional axis.","evidence":"MeRIP-seq/reporter for m6A; YTHDF2 and LRAT perturbation with ROS, NADP+/NADPH and clonogenic assays; spatial imaging; Co-IP/GST pull-down/SPR/CETSA/ChIP for Nrf2 interaction","pmids":["41579973","41993611"],"confidence":"Medium","gaps":["Functional consequence of the DHRS3–Nrf2 physical interaction unresolved","Single lab for each axis","Mechanism linking NADPH buffering to retinoid catalysis not fully integrated"]},{"year":null,"claim":"How DHRS3's multiple regulatory inputs (RA/RAR-RXR feedback, p53/p63, miR-223, m6A/YTHDF2, Nrf2) and its dual retinoid-reductase and NADPH/redox-buffering roles are integrated in specific tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the enzyme","Tissue-specific weighting of regulatory inputs unknown","Direct mechanistic role of the Nrf2 interaction undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,2,6,8]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,6,11]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[3,10,11]}],"pathway":[],"complexes":[],"partners":["YTHDF2","LRAT","NFE2L2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75911","full_name":"Short-chain dehydrogenase/reductase 3","aliases":["DD83.1","Retinal short-chain dehydrogenase/reductase 1","retSDR1","Retinol dehydrogenase 17","Short chain dehydrogenase/reductase family 16C member 1"],"length_aa":302,"mass_kda":33.5,"function":"Catalyzes the reduction of all-trans-retinal to all-trans-retinol in the presence of NADPH","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/O75911/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DHRS3","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DHRS3","total_profiled":1310},"omim":[{"mim_id":"621499","title":"CRANIOSYNOSTOSIS-SCOLIOSIS SYNDROME; CRSS","url":"https://www.omim.org/entry/621499"},{"mim_id":"612830","title":"SHORT-CHAIN DEHYDROGENASE/REDUCTASE FAMILY, MEMBER 3; DHRS3","url":"https://www.omim.org/entry/612830"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":238.1}],"url":"https://www.proteinatlas.org/search/DHRS3"},"hgnc":{"alias_symbol":["retSDR1","Rsdr1","SDR1","RDH17","SDR16C1","CNALPTC1"],"prev_symbol":[]},"alphafold":{"accession":"O75911","domains":[{"cath_id":"3.40.50.720","chopping":"35-302","consensus_level":"medium","plddt":95.1484,"start":35,"end":302}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75911","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75911-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75911-F1-predicted_aligned_error_v6.png","plddt_mean":94.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DHRS3","jax_strain_url":"https://www.jax.org/strain/search?query=DHRS3"},"sequence":{"accession":"O75911","fasta_url":"https://rest.uniprot.org/uniprotkb/O75911.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75911/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75911"}},"corpus_meta":[{"pmid":"24005908","id":"PMC_24005908","title":"The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development.","date":"2013","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24005908","citation_count":110,"is_preprint":false},{"pmid":"11861404","id":"PMC_11861404","title":"retSDR1, a short-chain retinol dehydrogenase/reductase, is retinoic acid-inducible and frequently deleted in human neuroblastoma cell lines.","date":"2002","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11861404","citation_count":68,"is_preprint":false},{"pmid":"21659514","id":"PMC_21659514","title":"p53-Inducible DHRS3 is an endoplasmic reticulum protein associated with lipid droplet accumulation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21659514","citation_count":60,"is_preprint":false},{"pmid":"24045938","id":"PMC_24045938","title":"Dhrs3 protein attenuates retinoic acid signaling and is required for early embryonic patterning.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24045938","citation_count":49,"is_preprint":false},{"pmid":"20543567","id":"PMC_20543567","title":"The retinal dehydrogenase/reductase retSDR1/DHRS3 gene is activated by p53 and p63 but not by mutants derived from tumors or EEC/ADULT malformation syndromes.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20543567","citation_count":35,"is_preprint":false},{"pmid":"29416932","id":"PMC_29416932","title":"Long noncoding RNA CNALPTC1 promotes cell proliferation and migration of papillary thyroid cancer via sponging miR-30 family.","date":"2018","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29416932","citation_count":34,"is_preprint":false},{"pmid":"22790594","id":"PMC_22790594","title":"DHRS3, a retinal reductase, is differentially regulated by retinoic acid and lipopolysaccharide-induced inflammation in THP-1 cells and rat liver.","date":"2012","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22790594","citation_count":33,"is_preprint":false},{"pmid":"29794437","id":"PMC_29794437","title":"MicroRNA-223 Suppresses Osteoblast Differentiation by Inhibiting DHRS3.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29794437","citation_count":31,"is_preprint":false},{"pmid":"33360372","id":"PMC_33360372","title":"Circ_DHRS3 positively regulates GREM1 expression by competitively targeting miR-183-5p to modulate IL-1β-administered chondrocyte proliferation, apoptosis and ECM degradation.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33360372","citation_count":26,"is_preprint":false},{"pmid":"33902658","id":"PMC_33902658","title":"Inhibition of retinoic acid receptor α phosphorylation represses the progression of triple-negative breast cancer via transactivating miR-3074-5p to target DHRS3.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33902658","citation_count":21,"is_preprint":false},{"pmid":"25451588","id":"PMC_25451588","title":"Molecular and biochemical characterisation of human short-chain dehydrogenase/reductase member 3 (DHRS3).","date":"2014","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/25451588","citation_count":20,"is_preprint":false},{"pmid":"39479752","id":"PMC_39479752","title":"The Lipid Droplet Protein DHRS3 Is a Regulator of Melanoma Cell State.","date":"2024","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/39479752","citation_count":8,"is_preprint":false},{"pmid":"36868551","id":"PMC_36868551","title":"Overexpressed miRNA-nov-1 promotes manganese-induced apoptosis in N27 cells by regulating Dhrs3 to activate mTOR signaling 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(MeD-seq)","date":"2024-08-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.29.610227","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14399,"output_tokens":3702,"usd":0.049363,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11384,"output_tokens":3514,"usd":0.072385,"stage2_stop_reason":"end_turn"},"total_usd":0.121748,"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\": 2013,\n      \"finding\": \"DHRS3 functions as a retinaldehyde reductase essential for preventing excess retinoic acid formation during embryonic development. Dhrs3-knockout mice show a 40% increase in ATRA levels, 60% decrease in retinol, and 55% decrease in retinyl esters, along with compensatory changes in ATRA synthetic/catabolic genes (Cyp26a1 upregulated 120%). Knockout embryos die late in gestation with cardiac outflow tract, septal, skeletal, and palate defects.\",\n      \"method\": \"Dhrs3-deficient mouse model with quantitative retinoid metabolite measurements and gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with specific quantitative phenotypic readouts, multiple orthogonal methods (metabolite measurement, gene expression), independently consistent with other studies\",\n      \"pmids\": [\"24005908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dhrs3 (Xenopus) attenuates retinoic acid signaling by reducing all-trans-retinal levels. Overexpression of Dhrs3 counteracted the effects of Aldh1a2 or Rdh10 overexpression on RA signaling. Morpholino knockdown of Dhrs3 caused shortened anteroposterior axis, reduced head structure, and defective convergent extension movement, phenocopying excess RA treatment.\",\n      \"method\": \"Xenopus gain-of-function (overexpression) and loss-of-function (antisense morpholino knockdown) with phenotypic analysis and animal cap assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss of function in Xenopus with defined pathway placement (antagonizing Aldh1a2/Rdh10), multiple phenotypic readouts\",\n      \"pmids\": [\"24045938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"retSDR1/DHRS3 (short-chain dehydrogenase/reductase) promotes accumulation of retinyl esters when overexpressed in SK-N-AS neuroblastoma cells exposed to physiological retinol concentrations, indicating it generates storage forms of retinol from retinal. Expression is strongly induced by retinoic acid in neuroblastoma cell lines.\",\n      \"method\": \"Exogenous overexpression of retSDR1 in SK-N-AS cells with retinyl ester measurement; retinoic acid treatment with expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression assay with functional metabolite readout, single lab, consistent with biochemical role\",\n      \"pmids\": [\"11861404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHRS3 is an endoplasmic reticulum (ER) protein targeted via an N-terminal ER targeting signal, and it localizes to focal points of lipid droplet budding and to the phospholipid monolayer of ER-derived lipid droplets. p53 promotes lipid droplet accumulation consistent with DHRS3 enrichment at these sites. DHRS3 is identified as a p53 target gene.\",\n      \"method\": \"Subcellular fractionation, fluorescence/confocal microscopy for ER and lipid droplet co-localization, p53 microarray target identification, p53 overexpression/activation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization by imaging/fractionation tied to functional consequence (lipid droplet accumulation), single lab, p53 target validated by microarray and functional assay\",\n      \"pmids\": [\"21659514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DHRS3/retSDR1 transcription is activated by p53 and TAp63γ through two separate response elements in the retSDR1 promoter. Both proteins bind the promoter in vitro and in vivo (ChIP). Tumor-derived p53 mutants and EEC syndrome-specific TAp63γ mutants fail to activate retSDR1 transcription. DNA damage leads to recruitment of p53 and p63 to the retSDR1 promoter.\",\n      \"method\": \"Promoter reporter assays, in vitro binding assays, chromatin immunoprecipitation (ChIP), mutagenesis of response elements, DNA damage induction\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding, ChIP in vivo, mutagenesis, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"20543567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DHRS3 mRNA is strongly induced (30–40 fold) by retinoic acid via RAR-α-selective signaling in THP-1 monocytes, and is suppressed >90% by LPS in rat liver. DHRS3 is a microsomal protein producing two major isoforms (~30 and ~35 kDa) detected by in vitro transcription-translation. DHRS3 mRNA is most abundant in rat adrenal gland, liver, and ovary.\",\n      \"method\": \"Microarray and RT-PCR for expression; in vitro transcription-translation; selective retinoid agonist treatment (Am580, RAR-α selective); rat tissue expression and LPS/RA treatment in vivo\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro transcription-translation plus pharmacological dissection of RAR subtype, single lab\",\n      \"pmids\": [\"22790594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Recombinant human DHRS3 is a microsomal, integral-membrane protein with C-terminus oriented toward the cytosol and preferring NADPH as cofactor. In addition to all-trans-retinal, DHRS3 metabolizes endogenous substrates including androstenedione, estrone, and DL-glyceraldehyde, and xenobiotics NNK and acetohexamide. The enzyme was purified and reconstituted in vitro for the first time.\",\n      \"method\": \"Recombinant protein expression, membrane topology determination, cofactor preference assays (NADPH vs. NADH), in vitro enzymatic assays with multiple substrates, purification and reconstitution\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted purified enzyme with multiple substrate assays and topology determination, single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"25451588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mouse Dhrs3 expression is directly regulated by the RAR/RXR complex through cis-regulatory elements in a negative feedback mechanism responsive to vitamin A/retinoic acid status, ensuring retinoic acid homeostasis.\",\n      \"method\": \"Reporter assays with cis-regulatory element mapping, vitamin A status manipulation in mice, RAR/RXR complex binding assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cis-element mapping with functional assays, single lab\",\n      \"pmids\": [\"39420244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human DHRS3 missense variant p.(Val171Met) reduces retinaldehyde-to-retinol reduction capacity in transfected cells, yielding reduced retinol and elevated RA. Additional missense variants p.(Val110Ile), p.(Gly115Asp), and p.(Glu244Gln) reduce DHRS3 catalytic activity in vitro and/or in vivo. Patients homozygous for the Val171Met variant have reduced plasma retinol and elevated RA. Biallelic loss of DHRS3 causes a congenital syndrome with coronal craniosynostosis, congenital heart disease, and scoliosis.\",\n      \"method\": \"Cell transfection with mutant DHRS3 constructs and retinoid metabolite quantification; plasma retinoid measurements in patients; in vitro enzymatic activity assays for mutants\",\n      \"journal\": \"Genetics in medicine open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro mutagenesis with functional enzymatic readout, confirmed with patient plasma metabolites and multiple variant alleles across independent families\",\n      \"pmids\": [\"40519748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-223 directly targets DHRS3 mRNA (confirmed by dual luciferase assay), suppressing DHRS3 expression and inhibiting osteoblast differentiation of human bone marrow-derived mesenchymal stem cells. Overexpression of DHRS3 promotes osteogenic differentiation (increased ALP activity, matrix calcification, Runx2/OPN/OCN expression), and rescue by DHRS3 cDNA reverses miR-223 inhibition.\",\n      \"method\": \"Dual luciferase reporter assay, miR-223 mimic/inhibitor transfection, DHRS3 overexpression, ALP staining, ARS staining, western blotting for differentiation markers\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct target validation by luciferase assay, gain/loss of function, rescue experiment; single lab\",\n      \"pmids\": [\"29794437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHRS3 localizes to lipid droplets in melanoma cells (confirmed by proteomics of the lipid droplet envelope). Increased DHRS3 expression drives MITFHI/melanocytic cells toward a more undifferentiated/invasive state via retinoic acid-mediated regulation of melanocytic genes.\",\n      \"method\": \"Proteomic analysis of lipid droplet envelope fractions from melanoma cells, DHRS3 overexpression with cell state and gene expression analysis\",\n      \"journal\": \"Pigment cell & melanoma research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomic fractionation confirming lipid droplet localization, gain-of-function with defined downstream pathway (RA signaling), single lab\",\n      \"pmids\": [\"39479752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DHRS3 protein is stabilized post-transcriptionally by YTHDF2, which recognizes an m6A-modified site in the DHRS3 3' UTR. After irradiation, DHRS3 localizes at ER-lipid droplet regions juxtaposed to mitochondria, facilitated by LRAT. DHRS3 depletion elevates ROS, disrupts NADP+/NADPH ratios, and abrogates radioprotective effects of YTHDF2. LRAT loss disperses ER-LD interfaces and mislocalizes DHRS3, impairing retinoid and NADPH buffering.\",\n      \"method\": \"MeRIP-seq, MeRIP-qPCR, reporter assays for m6A site validation; DHRS3 knockdown/YTHDF2 overexpression with ROS and clonogenic survival assays; spatial imaging of organelle contacts; LRAT perturbation; enforced mitochondrial targeting of DHRS3\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeRIP-seq, reporter, imaging, metabolic assays), single lab, 2026 publication\",\n      \"pmids\": [\"41579973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DHRS3 physically interacts with Nrf2 (shown by co-immunoprecipitation and GST pull-down). This protein-protein interaction can be disrupted by compound Cpd.51. DHRS3 expression is suppressed as a downstream target of Nrf2 transcriptional activity (Nrf2 activation reduces DHRS3).\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, surface plasmon resonance, cellular thermal shift assay, chromatin immunoprecipitation, RNA sequencing\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods to confirm interaction (Co-IP, pulldown, SPR, CETSA), single lab\",\n      \"pmids\": [\"41993611\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DHRS3 is a microsomal, integral-membrane short-chain dehydrogenase/reductase that uses NADPH to reduce all-trans-retinal to retinol (and also metabolizes androstenedione, estrone, and xenobiotics), thereby limiting excessive retinoic acid synthesis; its expression is transcriptionally induced by retinoic acid through RAR/RXR cis-elements (negative feedback), activated by p53 and TAp63γ via promoter response elements, and post-transcriptionally stabilized by YTHDF2-mediated m6A recognition; it localizes to the ER and lipid droplets (facilitated by LRAT at ER-LD-mitochondria interfaces) where it buffers NADPH/redox status, and loss of DHRS3 in mice or humans causes excess RA with embryonic/congenital defects including cardiac, skeletal, and craniofacial malformations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DHRS3 is a microsomal, integral-membrane short-chain dehydrogenase/reductase that uses NADPH to reduce all-trans-retinal to retinol, thereby constraining the synthesis of retinoic acid and serving as a central buffer of retinoid homeostasis during development [#0, #6]. The purified enzyme prefers NADPH over NADH and, beyond retinaldehyde, also reduces androstenedione, estrone, and xenobiotic substrates [#6]. Functionally, DHRS3 acts in opposition to the RA-generating machinery (Aldh1a2/Rdh10): its knockdown phenocopies excess RA while its overexpression counteracts retinal-driven RA signaling [#1], and in cell models it promotes accumulation of retinyl ester storage forms of retinol [#2]. This activity is embedded in negative-feedback control of RA: DHRS3 transcription is directly induced by retinoic acid through RAR/RXR cis-regulatory elements [#7], and it is additionally a transcriptional target of p53 and TAp63\\u03b3 acting through distinct promoter response elements following DNA damage [#4, #3]. DHRS3 localizes to the ER and to lipid droplets, including ER\\u2013lipid-droplet interfaces juxtaposed to mitochondria where it supports NADPH/redox buffering and limits ROS [#3, #11]. Loss-of-function in mice produces excess ATRA with cardiac outflow tract, septal, skeletal, and palate defects [#0], and biallelic catalytically impairing variants in humans cause a congenital syndrome of coronal craniosynostosis, congenital heart disease, and scoliosis with reduced plasma retinol and elevated RA [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that DHRS3/retSDR1 acts on retinoid metabolism by generating retinol storage forms and that its expression is responsive to retinoic acid, first linking the enzyme to vitamin A handling.\",\n      \"evidence\": \"Overexpression of retSDR1 in SK-N-AS neuroblastoma cells with retinyl ester measurement and RA-induction expression analysis\",\n      \"pmids\": [\"11861404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-only, no direct enzymatic kinetics\", \"Direction of reaction (retinal\\u2192retinol vs storage) inferred from metabolite pools\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the transcriptional control of DHRS3 by tumor-suppressor transcription factors, placing the gene downstream of p53/TAp63\\u03b3 stress and developmental signaling.\",\n      \"evidence\": \"Promoter reporter assays, in vitro binding, ChIP, response-element mutagenesis, and DNA damage induction\",\n      \"pmids\": [\"20543567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish the biochemical function of the DHRS3 protein itself\", \"Link between p53/p63 induction and retinoid outcome not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined DHRS3 subcellular localization to the ER and lipid droplets via an N-terminal targeting signal, connecting its activity to lipid-storage organelles and confirming it as a p53 target.\",\n      \"evidence\": \"Subcellular fractionation, confocal co-localization, p53 microarray target identification and activation experiments\",\n      \"pmids\": [\"21659514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic role of LD localization in catalysis not resolved\", \"Single lab\", \"Topology not yet determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed DHRS3 induction is RAR-\\u03b1-selective and that it is a microsomal protein, refining the receptor subtype driving its feedback regulation.\",\n      \"evidence\": \"Microarray/RT-PCR, in vitro transcription-translation, RAR-\\u03b1-selective agonist (Am580), and rat tissue/LPS/RA treatments in vivo\",\n      \"pmids\": [\"22790594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two isoforms detected but functional difference unknown\", \"Cis-elements not yet mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated in vivo that DHRS3 is a retinaldehyde reductase essential for limiting embryonic ATRA, resolving the physiological consequence of its enzymatic activity.\",\n      \"evidence\": \"Dhrs3-knockout mouse with quantitative retinoid metabolite measurement and RA gene-expression analysis; reciprocal Xenopus gain/loss-of-function antagonizing Aldh1a2/Rdh10\",\n      \"pmids\": [\"24005908\", \"24045938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro enzymatic reconstitution not yet performed\", \"Cofactor preference inferred not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Biochemically defined DHRS3 as an integral-membrane, NADPH-preferring reductase with a broad substrate range, providing the first reconstitution of purified enzyme.\",\n      \"evidence\": \"Recombinant expression, membrane topology determination, NADPH/NADH cofactor assays, multi-substrate enzymatic assays, purification and reconstitution\",\n      \"pmids\": [\"25451588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model\", \"Relative physiological importance of non-retinoid substrates unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended DHRS3 regulation to the post-transcriptional level and to a new cellular outcome, showing miR-223 represses DHRS3 to control osteoblast differentiation.\",\n      \"evidence\": \"Dual-luciferase target validation, miR-223 mimic/inhibitor, DHRS3 overexpression and rescue, differentiation marker assays in human MSCs\",\n      \"pmids\": [\"29794437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether retinoid metabolism mediates the osteogenic effect not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the direct RAR/RXR cis-regulatory feedback loop and added a tumor-context role for DHRS3 in driving melanoma cell-state plasticity.\",\n      \"evidence\": \"Reporter assays with cis-element mapping and vitamin-A manipulation in mice; lipid-droplet envelope proteomics and overexpression in melanoma cells\",\n      \"pmids\": [\"39420244\", \"39479752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAR/RXR element mapping in mouse; human conservation not addressed\", \"Melanoma role from gain-of-function only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established DHRS3 as a Mendelian disease gene, showing biallelic catalytically impairing variants cause a congenital craniofacial/cardiac/skeletal syndrome through excess RA.\",\n      \"evidence\": \"Cell transfection of mutant constructs with retinoid metabolite quantification, in vitro activity assays for multiple alleles, and patient plasma retinoid measurements\",\n      \"pmids\": [\"40519748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype\\u2013phenotype correlation across variants incomplete\", \"No structural rationale for specific missense effects\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected DHRS3 to redox buffering and organelle contact sites, showing m6A/YTHDF2 stabilization and LRAT-dependent ER-LD-mitochondria positioning underlie its radioprotective NADPH/ROS function, and identified an Nrf2 physical and transcriptional axis.\",\n      \"evidence\": \"MeRIP-seq/reporter for m6A; YTHDF2 and LRAT perturbation with ROS, NADP+/NADPH and clonogenic assays; spatial imaging; Co-IP/GST pull-down/SPR/CETSA/ChIP for Nrf2 interaction\",\n      \"pmids\": [\"41579973\", \"41993611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the DHRS3\\u2013Nrf2 physical interaction unresolved\", \"Single lab for each axis\", \"Mechanism linking NADPH buffering to retinoid catalysis not fully integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DHRS3's multiple regulatory inputs (RA/RAR-RXR feedback, p53/p63, miR-223, m6A/YTHDF2, Nrf2) and its dual retinoid-reductase and NADPH/redox-buffering roles are integrated in specific tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the enzyme\", \"Tissue-specific weighting of regulatory inputs unknown\", \"Direct mechanistic role of the Nrf2 interaction undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 6, 8]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [3, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1430728\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"YTHDF2\",\n      \"LRAT\",\n      \"NFE2L2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}