{"gene":"DHRS3","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2013,"finding":"DHRS3 functions as a retinaldehyde reductase in vivo; Dhrs3-knockout mouse embryos show 40% increase in ATRA, 60% decrease in retinol, and 55% decrease in retinyl esters, demonstrating that DHRS3 reduces retinaldehyde to retinol to prevent excess retinoic acid formation during embryogenesis.","method":"Dhrs3-deficient mouse model with quantitative retinoid measurements, expression analysis of RA synthetic/catabolic genes, and developmental phenotyping (cardiac, skeletal, palate defects)","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined biochemical and developmental phenotype, replicated by independent Xenopus study","pmids":["24005908"],"is_preprint":false},{"year":2013,"finding":"Dhrs3 (Xenopus ortholog) attenuates retinoic acid signaling by reducing all-trans-retinal levels; it counteracts Aldh1a2 and Rdh10 activity, and its knockdown causes shortened anteroposterior axis, reduced head structures, and defective convergent extension movement phenocopying excess RA treatment.","method":"Antisense morpholino knockdown in Xenopus embryos; overexpression epistasis with aldh1a2 and rdh10; animal cap assay; marker gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Xenopus with multiple orthogonal functional readouts, consistent with mouse KO data","pmids":["24045938"],"is_preprint":false},{"year":2014,"finding":"Human DHRS3 is a microsomal, integral-membrane protein with its C-terminus oriented toward the cytosol, prefers NADPH as cofactor, and reduces not only all-trans-retinal but also androstenedione, estrone, DL-glyceraldehyde, and xenobiotics (NNK, acetohexamide).","method":"Recombinant enzyme expression, membrane fractionation, topology analysis, cofactor preference assay, in vitro enzymatic activity assays with multiple substrates, purified/reconstituted enzyme preparation","journal":"Chemico-biological interactions","confidence":"High","confidence_rationale":"Tier 1 — reconstituted purified enzyme with in vitro substrate characterization and topology determination","pmids":["25451588"],"is_preprint":false},{"year":2011,"finding":"DHRS3 is an endoplasmic reticulum protein directed there by 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 the ER.","method":"Subcellular fractionation, fluorescence microscopy/co-localization, N-terminal signal sequence analysis, p53 induction experiments, microarray identification of DHRS3 as p53 target","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional link to lipid droplet dynamics, single lab","pmids":["21659514"],"is_preprint":false},{"year":2010,"finding":"DHRS3/retSDR1 transcription is directly activated by p53 and TAp63γ through two separate response elements in the retSDR1 promoter; both proteins bind the promoter in vitro and in vivo, and tumor-derived p53 mutants and EEC-syndrome p63 mutants fail to transactivate DHRS3.","method":"Promoter-reporter assays, chromatin immunoprecipitation (ChIP), in vitro DNA binding, mutagenesis of response elements, DNA damage induction with p53/p63 recruitment analysis","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro and in vivo promoter binding with mutagenesis and multiple p53/p63 variants tested","pmids":["20543567"],"is_preprint":false},{"year":2002,"finding":"Exogenous expression of retSDR1 (DHRS3) in SK-N-AS neuroblastoma cells induces accumulation of retinyl esters, demonstrating that DHRS3 generates retinol from retinal which is then stored as retinyl esters; DHRS3 is retinoic acid-inducible in neuroblastoma cell lines.","method":"Retinyl ester quantification after exogenous DHRS3 expression in SK-N-AS cells; RA-treatment expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct overexpression with biochemical readout (retinyl ester accumulation), single lab","pmids":["11861404"],"is_preprint":false},{"year":2012,"finding":"DHRS3 mRNA is induced 30–40-fold by all-trans-retinoic acid in THP-1 monocytes specifically via RARα (Am580-selective retinoid activates DHRS3; other retinoids do not); in rat liver, LPS-induced inflammation suppresses DHRS3 mRNA by >90%, overriding RA induction.","method":"Microarray and RT-qPCR in THP-1 cells, synthetic retinoid panel testing (RARα/β/γ selective), in vitro transcription-translation of rat DHRS3 cDNA, rat RA/LPS in vivo dosing with liver mRNA quantification","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (microarray, RT-qPCR, receptor-selective pharmacology, in vivo), single lab","pmids":["22790594"],"is_preprint":false},{"year":2024,"finding":"Mouse Dhrs3 expression is directly regulated by the RAR/RXR heterodimer complex through cis-regulatory elements in the Dhrs3 locus, establishing a negative feedback mechanism: retinoic acid induces Dhrs3, which reduces retinaldehyde to retinol, limiting further RA synthesis.","method":"Vitamin A status manipulation in mice, cis-regulatory element identification, RAR/RXR binding assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo vitamin A modulation with cis-regulatory element characterization, single lab","pmids":["39420244"],"is_preprint":false},{"year":2018,"finding":"miR-223 directly targets DHRS3 mRNA (confirmed by dual luciferase assay); miR-223 inhibition promotes osteogenic differentiation of hBMSCs via DHRS3 upregulation, and co-transfection of miR-223 agomir with DHRS3 cDNA rescues the differentiation phenotype to baseline.","method":"Dual luciferase reporter assay, miR-223 mimic/inhibitor transfection, DHRS3 overexpression, ALP/ARS staining, western blot for Runx2/OPN/OCN in hBMSCs","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — luciferase validation of direct targeting plus epistasis rescue experiment, single lab","pmids":["29794437"],"is_preprint":false},{"year":2024,"finding":"DHRS3 is enriched in lipid droplets of the MITF-low/undifferentiated melanoma cell state; overexpression of DHRS3 in MITF-high melanocytic cells drives them to a more undifferentiated/invasive state through retinoic acid-mediated regulation of melanocytic genes.","method":"Proteomic analysis of lipid droplet envelope in melanoma cell lines, DHRS3 overexpression with cell state marker analysis, retinoic acid pathway readouts","journal":"Pigment cell & melanoma research","confidence":"Medium","confidence_rationale":"Tier 2–3 — proteomics plus functional overexpression with defined pathway mechanism, single lab","pmids":["39479752"],"is_preprint":false},{"year":2025,"finding":"Biallelic hypomorphic DHRS3 variants in humans cause a developmental syndrome (coronal craniosynostosis, congenital heart disease, scoliosis); cells transfected with DHRS3-Val171Met show reduced retinaldehyde reduction capacity versus wild-type, and patient plasma exhibits reduced retinol and elevated retinoic acid, confirming the enzymatic role of DHRS3 in human retinoid homeostasis in vivo.","method":"Patient cohort analysis; in vitro DHRS3-Val171Met transfection retinaldehyde reduction assay; plasma retinoid metabolite quantification in patients vs. controls; DHRS3 mRNA quantification from whole blood","journal":"Genetics in medicine open","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzymatic activity of missense variant plus in vivo plasma retinoid measurements in human patients, multiple families","pmids":["40519748"],"is_preprint":false},{"year":2026,"finding":"DHRS3 protein interacts directly with Nrf2; disruption of this protein-protein interaction by compound Cpd.51 provides additional Nrf2-activating activity, and Nrf2 activation suppresses DHRS3 transcription, revealing a negative feedback loop between Nrf2 and 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 1–2 — multiple orthogonal binding methods confirming DHRS3-Nrf2 interaction, single lab","pmids":["41993611"],"is_preprint":false},{"year":2026,"finding":"YTHDF2 binds an m6A-modified site in the DHRS3 3' UTR to maintain DHRS3 protein expression after irradiation; LRAT enriches DHRS3 at ER-lipid droplet junctions adjacent to mitochondria, and DHRS3 depletion elevates ROS and disrupts NADP+/NADPH ratios, phenocopying radiosensitization.","method":"MeRIP-seq and MeRIP-qPCR identifying m6A site, reporter assay for YTHDF2 binding, spatial imaging of DHRS3/LRAT co-localization, DHRS3 and LRAT knockdown with ROS/NADPH measurement, enforced mitochondrial DHRS3 targeting rescue","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods for m6A-YTHDF2-DHRS3 axis and organelle localization with functional redox readouts, single lab","pmids":["41579973"],"is_preprint":false}],"current_model":"DHRS3 is a microsomal, integral-membrane short-chain dehydrogenase/reductase that uses NADPH to reduce all-trans-retinaldehyde to retinol (and can also act on androstenedione, estrone, and xenobiotics), localizes to the ER and lipid droplet surface, is transcriptionally induced by retinoic acid via RAR/RXR and by p53/p63 through defined promoter response elements as a negative feedback mechanism, and is essential for preventing excess retinoic acid accumulation during vertebrate embryogenesis; loss-of-function in mice and humans causes retinoic acid embryopathy with cardiac, skeletal, and craniofacial defects."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that DHRS3 generates retinol for storage: overexpression of DHRS3 in neuroblastoma cells caused retinyl ester accumulation, providing the first direct evidence that the enzyme acts as a retinaldehyde reductase and that it is retinoic acid–inducible, suggesting a feedback role.","evidence":"Retinyl ester quantification after DHRS3 overexpression in SK-N-AS neuroblastoma cells; RA-treatment expression analysis","pmids":["11861404"],"confidence":"Medium","gaps":["Enzymatic activity not demonstrated with purified protein","In vivo significance unknown at this point","Substrate specificity beyond retinal not tested"]},{"year":2010,"claim":"Linking DHRS3 transcription to the p53/p63 tumor-suppressor axis: identification of two functional p53/TAp63γ response elements in the DHRS3 promoter showed that DNA-damage pathways directly activate retinaldehyde reduction, connecting retinoid metabolism to stress signaling.","evidence":"Promoter-reporter assays, ChIP, in vitro DNA binding, response element mutagenesis, testing of tumor-derived p53 and EEC-syndrome p63 mutants","pmids":["20543567"],"confidence":"High","gaps":["Physiological consequence of p53-driven DHRS3 induction on retinoid levels not measured","Relationship to cell-cycle arrest or apoptosis unclear"]},{"year":2011,"claim":"Defining DHRS3 subcellular localization: demonstration that DHRS3 resides in the ER directed by an N-terminal signal and concentrates at ER–lipid droplet budding sites revealed the compartment where retinaldehyde reduction and retinol storage are spatially coupled.","evidence":"Subcellular fractionation, fluorescence microscopy co-localization, N-terminal signal analysis in cultured cells","pmids":["21659514"],"confidence":"Medium","gaps":["ER–lipid droplet targeting mechanism not molecularly defined","Functional interaction with lipid droplet biogenesis machinery not characterized"]},{"year":2012,"claim":"Identifying the retinoic acid receptor isoform responsible for DHRS3 induction: RAR α-selective agonist recapitulated the 30–40-fold RA-mediated DHRS3 mRNA induction in monocytes, and inflammation (LPS) suppressed DHRS3 by >90%, revealing that the feedback loop is receptor-specific and context-dependent.","evidence":"Microarray and RT-qPCR in THP-1 cells with receptor-selective retinoid panel; rat in vivo LPS/RA dosing","pmids":["22790594"],"confidence":"Medium","gaps":["Direct RARα binding to DHRS3 cis-regulatory elements not shown in this study","Mechanism of LPS-mediated suppression not resolved"]},{"year":2013,"claim":"Proving DHRS3 is essential for retinoid homeostasis in vivo: Dhrs3-knockout mouse embryos accumulated 40% more ATRA, lost 60% of retinol, and exhibited cardiac/skeletal/palatal defects; independently, Xenopus Dhrs3 morphants phenocopied excess RA, establishing DHRS3 as a non-redundant developmental retinaldehyde reductase.","evidence":"Dhrs3-KO mouse with quantitative retinoid profiling and developmental phenotyping; Xenopus morpholino knockdown with epistasis analysis against Aldh1a2/Rdh10","pmids":["24005908","24045938"],"confidence":"High","gaps":["Redundancy with other retinaldehyde reductases (e.g., RDH10 reverse activity) not fully quantified","Tissue-specific contributions during organogenesis not mapped"]},{"year":2014,"claim":"Biochemical characterization of purified human DHRS3: reconstituted enzyme demonstrated NADPH preference, integral-membrane topology with cytosolic C-terminus, and activity toward steroids (androstenedione, estrone) and xenobiotics beyond retinal, establishing DHRS3 as a multi-substrate reductase.","evidence":"Recombinant expression, membrane fractionation, topology analysis, cofactor preference assay, in vitro activity assays with purified enzyme","pmids":["25451588"],"confidence":"High","gaps":["Kinetic parameters for non-retinoid substrates not compared to retinal to assess physiological relevance","No structural model available"]},{"year":2018,"claim":"Revealing post-transcriptional regulation of DHRS3: miR-223 directly targets the DHRS3 3ʹ UTR, and modulation of miR-223 levels controls osteogenic differentiation of mesenchymal stem cells through DHRS3-dependent retinoid signaling.","evidence":"Dual luciferase reporter assay, miR-223 mimic/inhibitor transfection with DHRS3 rescue, osteogenic marker analysis in hBMSCs","pmids":["29794437"],"confidence":"Medium","gaps":["In vivo relevance of miR-223–DHRS3 axis in bone formation not tested","Retinoid metabolite levels not directly measured"]},{"year":2024,"claim":"Closing the negative-feedback loop at the chromatin level: RAR/RXR heterodimers were shown to bind cis-regulatory elements within the Dhrs3 locus, and DHRS3 was found enriched in lipid droplets of undifferentiated melanoma cells where its overexpression drives cell-state transitions via RA pathway modulation.","evidence":"Vitamin A manipulation in mice with RAR/RXR binding assays; melanoma lipid droplet proteomics and DHRS3 overexpression with cell-state markers","pmids":["39420244","39479752"],"confidence":"Medium","gaps":["Exact cis-regulatory element sequences and their necessity not dissected by deletion","Causality in melanoma phenotype switching needs in vivo validation"]},{"year":2025,"claim":"Establishing human disease causation: biallelic DHRS3 hypomorphic variants (including Val171Met) cause a Mendelian syndrome of craniosynostosis, congenital heart disease, and scoliosis; patient plasma showed reduced retinol and elevated RA, and the variant enzyme had diminished retinaldehyde reductase activity, confirming the mouse-predicted essentiality in humans.","evidence":"Multi-family patient cohort, in vitro enzymatic assay of DHRS3-V171M, plasma retinoid metabolite quantification","pmids":["40519748"],"confidence":"High","gaps":["Genotype–phenotype correlation across different variant classes not yet established","Rescue experiments in patient-derived cells not reported"]},{"year":2026,"claim":"Uncovering two new regulatory axes: DHRS3 protein directly interacts with Nrf2 (forming a mutual negative-feedback loop), and YTHDF2 maintains DHRS3 expression through m6A modification of its 3ʹ UTR; LRAT co-localizes DHRS3 to ER–lipid droplet–mitochondria contact sites where its loss elevates ROS and disrupts NADP⁺/NADPH balance.","evidence":"Co-IP, GST pull-down, SPR, CETSA for Nrf2 interaction; MeRIP-seq/qPCR and reporter assays for m6A-YTHDF2 axis; spatial imaging, DHRS3/LRAT knockdown with ROS/NADPH measurements","pmids":["41993611","41579973"],"confidence":"Medium","gaps":["DHRS3–Nrf2 interaction domain and stoichiometry not mapped","Whether DHRS3's redox role at mitochondria-adjacent sites is retinoid-dependent or independent not resolved","Single-lab findings for each axis await independent replication"]},{"year":null,"claim":"Key unresolved questions include: the three-dimensional structure of DHRS3, the relative physiological importance of its non-retinoid substrates, the molecular basis of tissue-specific regulation during organogenesis, and whether the Nrf2 interaction and m6A regulation are relevant in developmental contexts.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure solved","Physiological relevance of steroid/xenobiotic reduction versus retinaldehyde reduction not delineated","Conditional tissue-specific knockout studies not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,2,5,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3,12]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[3,9,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2,5,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10]}],"complexes":[],"partners":["NRF2","LRAT","YTHDF2","TP53","TP63","RARA"],"other_free_text":[]},"mechanistic_narrative":"DHRS3 is an NADPH-dependent short-chain dehydrogenase/reductase that reduces all-trans-retinaldehyde to retinol, functioning as a critical negative-feedback regulator of retinoic acid biosynthesis during embryonic development and adult tissue homeostasis. The enzyme is an integral ER membrane protein with its C-terminus facing the cytosol; it is also enriched at ER–lipid droplet junctions where it cooperates with LRAT for retinol esterification and storage, and its depletion elevates cellular ROS and disrupts NADP⁺/NADPH balance [PMID:25451588, PMID:21659514, PMID:41579973]. DHRS3 transcription is strongly induced by retinoic acid via RAR/RXR heterodimers, and independently by p53 and TAp63γ through defined promoter response elements, embedding the enzyme in both retinoid and DNA-damage signaling networks [PMID:39420244, PMID:20543567, PMID:22790594]. Biallelic loss-of-function DHRS3 variants in humans cause a developmental syndrome featuring craniosynostosis, congenital heart disease, and scoliosis, mirroring the cardiac, skeletal, and craniofacial defects observed in Dhrs3-knockout mice due to excess retinoic acid accumulation [PMID:40519748, PMID:24005908]."},"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":59,"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":48,"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":"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":25,"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":19,"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":19,"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 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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":12938,"output_tokens":3337,"usd":0.044435},"stage2":{"model":"claude-opus-4-6","input_tokens":6731,"output_tokens":3071,"usd":0.165645},"total_usd":0.21008,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"DHRS3 functions as a retinaldehyde reductase in vivo; Dhrs3-knockout mouse embryos show 40% increase in ATRA, 60% decrease in retinol, and 55% decrease in retinyl esters, demonstrating that DHRS3 reduces retinaldehyde to retinol to prevent excess retinoic acid formation during embryogenesis.\",\n      \"method\": \"Dhrs3-deficient mouse model with quantitative retinoid measurements, expression analysis of RA synthetic/catabolic genes, and developmental phenotyping (cardiac, skeletal, palate defects)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined biochemical and developmental phenotype, replicated by independent Xenopus study\",\n      \"pmids\": [\"24005908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dhrs3 (Xenopus ortholog) attenuates retinoic acid signaling by reducing all-trans-retinal levels; it counteracts Aldh1a2 and Rdh10 activity, and its knockdown causes shortened anteroposterior axis, reduced head structures, and defective convergent extension movement phenocopying excess RA treatment.\",\n      \"method\": \"Antisense morpholino knockdown in Xenopus embryos; overexpression epistasis with aldh1a2 and rdh10; animal cap assay; marker gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Xenopus with multiple orthogonal functional readouts, consistent with mouse KO data\",\n      \"pmids\": [\"24045938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human DHRS3 is a microsomal, integral-membrane protein with its C-terminus oriented toward the cytosol, prefers NADPH as cofactor, and reduces not only all-trans-retinal but also androstenedione, estrone, DL-glyceraldehyde, and xenobiotics (NNK, acetohexamide).\",\n      \"method\": \"Recombinant enzyme expression, membrane fractionation, topology analysis, cofactor preference assay, in vitro enzymatic activity assays with multiple substrates, purified/reconstituted enzyme preparation\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted purified enzyme with in vitro substrate characterization and topology determination\",\n      \"pmids\": [\"25451588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHRS3 is an endoplasmic reticulum protein directed there by 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 the ER.\",\n      \"method\": \"Subcellular fractionation, fluorescence microscopy/co-localization, N-terminal signal sequence analysis, p53 induction experiments, microarray identification of DHRS3 as p53 target\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional link to lipid droplet dynamics, single lab\",\n      \"pmids\": [\"21659514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DHRS3/retSDR1 transcription is directly activated by p53 and TAp63γ through two separate response elements in the retSDR1 promoter; both proteins bind the promoter in vitro and in vivo, and tumor-derived p53 mutants and EEC-syndrome p63 mutants fail to transactivate DHRS3.\",\n      \"method\": \"Promoter-reporter assays, chromatin immunoprecipitation (ChIP), in vitro DNA binding, mutagenesis of response elements, DNA damage induction with p53/p63 recruitment analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro and in vivo promoter binding with mutagenesis and multiple p53/p63 variants tested\",\n      \"pmids\": [\"20543567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Exogenous expression of retSDR1 (DHRS3) in SK-N-AS neuroblastoma cells induces accumulation of retinyl esters, demonstrating that DHRS3 generates retinol from retinal which is then stored as retinyl esters; DHRS3 is retinoic acid-inducible in neuroblastoma cell lines.\",\n      \"method\": \"Retinyl ester quantification after exogenous DHRS3 expression in SK-N-AS cells; RA-treatment expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct overexpression with biochemical readout (retinyl ester accumulation), single lab\",\n      \"pmids\": [\"11861404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DHRS3 mRNA is induced 30–40-fold by all-trans-retinoic acid in THP-1 monocytes specifically via RARα (Am580-selective retinoid activates DHRS3; other retinoids do not); in rat liver, LPS-induced inflammation suppresses DHRS3 mRNA by >90%, overriding RA induction.\",\n      \"method\": \"Microarray and RT-qPCR in THP-1 cells, synthetic retinoid panel testing (RARα/β/γ selective), in vitro transcription-translation of rat DHRS3 cDNA, rat RA/LPS in vivo dosing with liver mRNA quantification\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (microarray, RT-qPCR, receptor-selective pharmacology, in vivo), single lab\",\n      \"pmids\": [\"22790594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mouse Dhrs3 expression is directly regulated by the RAR/RXR heterodimer complex through cis-regulatory elements in the Dhrs3 locus, establishing a negative feedback mechanism: retinoic acid induces Dhrs3, which reduces retinaldehyde to retinol, limiting further RA synthesis.\",\n      \"method\": \"Vitamin A status manipulation in mice, cis-regulatory element identification, RAR/RXR binding assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo vitamin A modulation with cis-regulatory element characterization, single lab\",\n      \"pmids\": [\"39420244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-223 directly targets DHRS3 mRNA (confirmed by dual luciferase assay); miR-223 inhibition promotes osteogenic differentiation of hBMSCs via DHRS3 upregulation, and co-transfection of miR-223 agomir with DHRS3 cDNA rescues the differentiation phenotype to baseline.\",\n      \"method\": \"Dual luciferase reporter assay, miR-223 mimic/inhibitor transfection, DHRS3 overexpression, ALP/ARS staining, western blot for Runx2/OPN/OCN in hBMSCs\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — luciferase validation of direct targeting plus epistasis rescue experiment, single lab\",\n      \"pmids\": [\"29794437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHRS3 is enriched in lipid droplets of the MITF-low/undifferentiated melanoma cell state; overexpression of DHRS3 in MITF-high melanocytic cells drives them to a more undifferentiated/invasive state through retinoic acid-mediated regulation of melanocytic genes.\",\n      \"method\": \"Proteomic analysis of lipid droplet envelope in melanoma cell lines, DHRS3 overexpression with cell state marker analysis, retinoic acid pathway readouts\",\n      \"journal\": \"Pigment cell & melanoma research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — proteomics plus functional overexpression with defined pathway mechanism, single lab\",\n      \"pmids\": [\"39479752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic hypomorphic DHRS3 variants in humans cause a developmental syndrome (coronal craniosynostosis, congenital heart disease, scoliosis); cells transfected with DHRS3-Val171Met show reduced retinaldehyde reduction capacity versus wild-type, and patient plasma exhibits reduced retinol and elevated retinoic acid, confirming the enzymatic role of DHRS3 in human retinoid homeostasis in vivo.\",\n      \"method\": \"Patient cohort analysis; in vitro DHRS3-Val171Met transfection retinaldehyde reduction assay; plasma retinoid metabolite quantification in patients vs. controls; DHRS3 mRNA quantification from whole blood\",\n      \"journal\": \"Genetics in medicine open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic activity of missense variant plus in vivo plasma retinoid measurements in human patients, multiple families\",\n      \"pmids\": [\"40519748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DHRS3 protein interacts directly with Nrf2; disruption of this protein-protein interaction by compound Cpd.51 provides additional Nrf2-activating activity, and Nrf2 activation suppresses DHRS3 transcription, revealing a negative feedback loop between Nrf2 and 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 1–2 — multiple orthogonal binding methods confirming DHRS3-Nrf2 interaction, single lab\",\n      \"pmids\": [\"41993611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YTHDF2 binds an m6A-modified site in the DHRS3 3' UTR to maintain DHRS3 protein expression after irradiation; LRAT enriches DHRS3 at ER-lipid droplet junctions adjacent to mitochondria, and DHRS3 depletion elevates ROS and disrupts NADP+/NADPH ratios, phenocopying radiosensitization.\",\n      \"method\": \"MeRIP-seq and MeRIP-qPCR identifying m6A site, reporter assay for YTHDF2 binding, spatial imaging of DHRS3/LRAT co-localization, DHRS3 and LRAT knockdown with ROS/NADPH measurement, enforced mitochondrial DHRS3 targeting rescue\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods for m6A-YTHDF2-DHRS3 axis and organelle localization with functional redox readouts, single lab\",\n      \"pmids\": [\"41579973\"],\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-retinaldehyde to retinol (and can also act on androstenedione, estrone, and xenobiotics), localizes to the ER and lipid droplet surface, is transcriptionally induced by retinoic acid via RAR/RXR and by p53/p63 through defined promoter response elements as a negative feedback mechanism, and is essential for preventing excess retinoic acid accumulation during vertebrate embryogenesis; loss-of-function in mice and humans causes retinoic acid embryopathy with cardiac, skeletal, and craniofacial defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DHRS3 is an NADPH-dependent short-chain dehydrogenase/reductase that reduces all-trans-retinaldehyde to retinol, functioning as a critical negative-feedback regulator of retinoic acid biosynthesis during embryonic development and adult tissue homeostasis. The enzyme is an integral ER membrane protein with its C-terminus facing the cytosol; it is also enriched at ER–lipid droplet junctions where it cooperates with LRAT for retinol esterification and storage, and its depletion elevates cellular ROS and disrupts NADP⁺/NADPH balance [PMID:25451588, PMID:21659514, PMID:41579973]. DHRS3 transcription is strongly induced by retinoic acid via RAR/RXR heterodimers, and independently by p53 and TAp63γ through defined promoter response elements, embedding the enzyme in both retinoid and DNA-damage signaling networks [PMID:39420244, PMID:20543567, PMID:22790594]. Biallelic loss-of-function DHRS3 variants in humans cause a developmental syndrome featuring craniosynostosis, congenital heart disease, and scoliosis, mirroring the cardiac, skeletal, and craniofacial defects observed in Dhrs3-knockout mice due to excess retinoic acid accumulation [PMID:40519748, PMID:24005908].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that DHRS3 generates retinol for storage: overexpression of DHRS3 in neuroblastoma cells caused retinyl ester accumulation, providing the first direct evidence that the enzyme acts as a retinaldehyde reductase and that it is retinoic acid–inducible, suggesting a feedback role.\",\n      \"evidence\": \"Retinyl ester quantification after DHRS3 overexpression in SK-N-AS neuroblastoma cells; RA-treatment expression analysis\",\n      \"pmids\": [\"11861404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic activity not demonstrated with purified protein\", \"In vivo significance unknown at this point\", \"Substrate specificity beyond retinal not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking DHRS3 transcription to the p53/p63 tumor-suppressor axis: identification of two functional p53/TAp63γ response elements in the DHRS3 promoter showed that DNA-damage pathways directly activate retinaldehyde reduction, connecting retinoid metabolism to stress signaling.\",\n      \"evidence\": \"Promoter-reporter assays, ChIP, in vitro DNA binding, response element mutagenesis, testing of tumor-derived p53 and EEC-syndrome p63 mutants\",\n      \"pmids\": [\"20543567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of p53-driven DHRS3 induction on retinoid levels not measured\", \"Relationship to cell-cycle arrest or apoptosis unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining DHRS3 subcellular localization: demonstration that DHRS3 resides in the ER directed by an N-terminal signal and concentrates at ER–lipid droplet budding sites revealed the compartment where retinaldehyde reduction and retinol storage are spatially coupled.\",\n      \"evidence\": \"Subcellular fractionation, fluorescence microscopy co-localization, N-terminal signal analysis in cultured cells\",\n      \"pmids\": [\"21659514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ER–lipid droplet targeting mechanism not molecularly defined\", \"Functional interaction with lipid droplet biogenesis machinery not characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying the retinoic acid receptor isoform responsible for DHRS3 induction: RAR α-selective agonist recapitulated the 30–40-fold RA-mediated DHRS3 mRNA induction in monocytes, and inflammation (LPS) suppressed DHRS3 by >90%, revealing that the feedback loop is receptor-specific and context-dependent.\",\n      \"evidence\": \"Microarray and RT-qPCR in THP-1 cells with receptor-selective retinoid panel; rat in vivo LPS/RA dosing\",\n      \"pmids\": [\"22790594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RARα binding to DHRS3 cis-regulatory elements not shown in this study\", \"Mechanism of LPS-mediated suppression not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Proving DHRS3 is essential for retinoid homeostasis in vivo: Dhrs3-knockout mouse embryos accumulated 40% more ATRA, lost 60% of retinol, and exhibited cardiac/skeletal/palatal defects; independently, Xenopus Dhrs3 morphants phenocopied excess RA, establishing DHRS3 as a non-redundant developmental retinaldehyde reductase.\",\n      \"evidence\": \"Dhrs3-KO mouse with quantitative retinoid profiling and developmental phenotyping; Xenopus morpholino knockdown with epistasis analysis against Aldh1a2/Rdh10\",\n      \"pmids\": [\"24005908\", \"24045938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with other retinaldehyde reductases (e.g., RDH10 reverse activity) not fully quantified\", \"Tissue-specific contributions during organogenesis not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Biochemical characterization of purified human DHRS3: reconstituted enzyme demonstrated NADPH preference, integral-membrane topology with cytosolic C-terminus, and activity toward steroids (androstenedione, estrone) and xenobiotics beyond retinal, establishing DHRS3 as a multi-substrate reductase.\",\n      \"evidence\": \"Recombinant expression, membrane fractionation, topology analysis, cofactor preference assay, in vitro activity assays with purified enzyme\",\n      \"pmids\": [\"25451588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic parameters for non-retinoid substrates not compared to retinal to assess physiological relevance\", \"No structural model available\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealing post-transcriptional regulation of DHRS3: miR-223 directly targets the DHRS3 3ʹ UTR, and modulation of miR-223 levels controls osteogenic differentiation of mesenchymal stem cells through DHRS3-dependent retinoid signaling.\",\n      \"evidence\": \"Dual luciferase reporter assay, miR-223 mimic/inhibitor transfection with DHRS3 rescue, osteogenic marker analysis in hBMSCs\",\n      \"pmids\": [\"29794437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of miR-223–DHRS3 axis in bone formation not tested\", \"Retinoid metabolite levels not directly measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Closing the negative-feedback loop at the chromatin level: RAR/RXR heterodimers were shown to bind cis-regulatory elements within the Dhrs3 locus, and DHRS3 was found enriched in lipid droplets of undifferentiated melanoma cells where its overexpression drives cell-state transitions via RA pathway modulation.\",\n      \"evidence\": \"Vitamin A manipulation in mice with RAR/RXR binding assays; melanoma lipid droplet proteomics and DHRS3 overexpression with cell-state markers\",\n      \"pmids\": [\"39420244\", \"39479752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exact cis-regulatory element sequences and their necessity not dissected by deletion\", \"Causality in melanoma phenotype switching needs in vivo validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing human disease causation: biallelic DHRS3 hypomorphic variants (including Val171Met) cause a Mendelian syndrome of craniosynostosis, congenital heart disease, and scoliosis; patient plasma showed reduced retinol and elevated RA, and the variant enzyme had diminished retinaldehyde reductase activity, confirming the mouse-predicted essentiality in humans.\",\n      \"evidence\": \"Multi-family patient cohort, in vitro enzymatic assay of DHRS3-V171M, plasma retinoid metabolite quantification\",\n      \"pmids\": [\"40519748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–phenotype correlation across different variant classes not yet established\", \"Rescue experiments in patient-derived cells not reported\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Uncovering two new regulatory axes: DHRS3 protein directly interacts with Nrf2 (forming a mutual negative-feedback loop), and YTHDF2 maintains DHRS3 expression through m6A modification of its 3ʹ UTR; LRAT co-localizes DHRS3 to ER–lipid droplet–mitochondria contact sites where its loss elevates ROS and disrupts NADP⁺/NADPH balance.\",\n      \"evidence\": \"Co-IP, GST pull-down, SPR, CETSA for Nrf2 interaction; MeRIP-seq/qPCR and reporter assays for m6A-YTHDF2 axis; spatial imaging, DHRS3/LRAT knockdown with ROS/NADPH measurements\",\n      \"pmids\": [\"41993611\", \"41579973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DHRS3–Nrf2 interaction domain and stoichiometry not mapped\", \"Whether DHRS3's redox role at mitochondria-adjacent sites is retinoid-dependent or independent not resolved\", \"Single-lab findings for each axis await independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the three-dimensional structure of DHRS3, the relative physiological importance of its non-retinoid substrates, the molecular basis of tissue-specific regulation during organogenesis, and whether the Nrf2 interaction and m6A regulation are relevant in developmental contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure solved\", \"Physiological relevance of steroid/xenobiotic reduction versus retinaldehyde reduction not delineated\", \"Conditional tissue-specific knockout studies not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [3, 9, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NRF2\",\n      \"LRAT\",\n      \"YTHDF2\",\n      \"TP53\",\n      \"TP63\",\n      \"RARA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}