{"gene":"MSMO1","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":1996,"finding":"ERG25 (yeast ortholog of MSMO1) encodes a C-4 sterol methyl oxidase that catalyzes the first of three enzymatic steps required to remove the two C-4 methyl groups in sterol biosynthesis. The protein contains a C-terminal ER retrieval signal (KKXX) and three histidine-rich clusters found in eukaryotic membrane desaturases and bacterial alkane hydroxylases, consistent with a nonheme iron-binding mechanism. Disruption of ERG25 leads to accumulation of 4,4-dimethylzymosterol.","method":"Genetic complementation, mutagenesis, sterol profile analysis by disruption mutant","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional complementation, disruptant sterol profiling, and sequence-based mechanistic annotation replicated across two independent 1996 papers","pmids":["8552601"],"is_preprint":false},{"year":1996,"finding":"The human homolog of ERG25 (MSMO1/SC4MOL) was cloned, sequenced, and mapped to chromosome 4q32-34. Western analysis showed two proteins of 34 and 75 kDa; both are membrane-bound and contain one N-glycosyl unit. Immunofluorescence localized the proteins to the endoplasmic reticulum and plasma membrane. ERG25 protein levels are regulated by an end product of the ergosterol pathway rather than by iron.","method":"Western blot, immunofluorescence, subcellular fractionation, glycosylation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (ER/PM), multiple methods (WB, IF, fractionation) in a single lab","pmids":["8663358"],"is_preprint":false},{"year":2000,"finding":"A temperature-sensitive point mutation within the histidine-cluster region of Candida albicans Erg25p (ortholog of MSMO1) causes conditional lethality, confirming that the histidine-rich clusters are functionally essential for C-4 sterol methyl oxidase activity.","method":"Random mutagenesis, temperature-sensitive allele rescue, sequence analysis","journal":"Lipids","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — active-site mutagenesis implication via ts allele, single lab study","pmids":["10783002"],"is_preprint":false},{"year":2002,"finding":"Temperature-sensitive erg25 mutations including substitutions N48D, V133A, and F135S cause accumulation of 4,4-dimethylzymosterol at non-permissive temperature, confirming ERG25 is required for C-4 demethylation and that these residues are important for enzyme function.","method":"Random mutagenesis, sterol profiling at non-permissive temperature","journal":"The Journal of antibiotics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with defined substrate accumulation readout, single lab","pmids":["12546417"],"is_preprint":false},{"year":1997,"finding":"Genetic epistasis analysis in S. cerevisiae shows that erg25 auxotrophy can be suppressed by combining erg11 with leaky heme biosynthesis mutations (slu1/slu2, alleles of HEM2 and HEM4), resulting in accumulation of lanosterol which supports growth. This places ERG25 downstream of lanosterol in the ergosterol pathway and demonstrates that lanosterol can substitute for ergosterol under these conditions.","method":"Genetic epistasis, suppressor screen, sterol profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple defined mutations, sterol profiling, functionally validated pathway position","pmids":["9326581"],"is_preprint":false},{"year":2011,"finding":"Loss-of-function mutations in human SC4MOL (MSMO1) cause accumulation of C4-methylsterols (meiosis-activating sterols, MASs). These accumulated MASs act as ligands for liver X receptors LXRα and LXRβ, leading to cell overproliferation in skin and blood and substantially altered immunocyte phenotype and in vitro function. This establishes MSMO1 as the enzyme catalyzing C4-methylsterol demethylation in human cholesterol synthesis.","method":"Patient mutation identification, biochemical sterol analysis, cell proliferation assays, immunocyte functional assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — human loss-of-function with defined biochemical substrate accumulation, LXR ligand mechanism, multiple orthogonal functional readouts","pmids":["21285510"],"is_preprint":false},{"year":2003,"finding":"ERG25/SC4MOL expression in vascular endothelial and smooth muscle cells is downregulated by LDL in a time- and dose-dependent manner. This downregulation is mediated through SREBP-2: LDL reduces SREBP-2 mRNA, and overexpression of SREBP-2 blocks LDL-induced ERG25 downregulation. An inhibitor of SREBP catabolism abolishes LDL-induced ERG25 downregulation.","method":"RT-PCR, Western blot, EMSA, transient transfection with SREBP-2 overexpression, pharmacological inhibitor","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation mechanism established by multiple methods (RT-PCR, EMSA, overexpression rescue), single lab","pmids":["12667960"],"is_preprint":false},{"year":2020,"finding":"Yeast Erg25 (ortholog of MSMO1) is a substrate for ER-associated degradation (ERAD): it is ubiquitinated, associates with stalled proteasomes, and its degradation depends on ERAD-associated ubiquitin ligases. Its turnover is regulated by sterol synthesis levels.","method":"Substrate trapping proteomics, affinity isolation, LC-MS/MS, ubiquitination assay, genetic epistasis with ERAD ubiquitin ligase mutants","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (proteomics, ubiquitination, genetic epistasis with ERAD machinery), single lab but rigorous","pmids":["32868373"],"is_preprint":false},{"year":2023,"finding":"Human SC4MOL (MSMO1) protein is rapidly turned over and is a substrate of the E3 ubiquitin ligase MARCHF6. Sterol depletion stabilizes SC4MOL protein levels, while sterol excess downregulates both SC4MOL transcript and protein. SC4MOL depletion by siRNA causes a significant decrease in total cellular cholesterol, identifying it as the most regulated enzyme in the C4-demethylation complex.","method":"siRNA knockdown, sterol manipulation, protein stability assays, cholesterol measurement in cultured mammalian cells (human and CHO)","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MARCHF6 as E3 ligase substrate established with sterol manipulation and KD phenotype, two cell line systems, multiple orthogonal readouts","pmids":["36958722"],"is_preprint":false},{"year":2021,"finding":"Genetic suppression of SC4MOL (MSMO1) increases oligodendrocyte formation from progenitor cells. The mechanism involves cellular accumulation of SC4MOL's 8,9-unsaturated sterol substrates, as exogenous addition of purified SC4MOL substrates (but not their 8,9-saturated analogs) promotes oligodendrocyte differentiation. A selective SC4MOL inhibitor (CW4142) induces accumulation of SC4MOL's sterol substrates in mouse brain in vivo.","method":"Genetic suppression, small-molecule inhibitors, exogenous sterol addition, in vivo brain sterol profiling","journal":"RSC chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological convergent evidence, substrate rescue experiment distinguishes saturated vs unsaturated analogs, in vivo validation","pmids":["35128409"],"is_preprint":false},{"year":2018,"finding":"MSMO1 overexpression inhibits 3T3-L1 adipogenesis and downregulates adipogenic marker genes, while MSMO1 knockdown has the opposite effect. MSMO1 and its partner NSDHL show a synergized (co-regulated) expression pattern during adipogenesis.","method":"Overexpression, siRNA knockdown, RNA-Seq, Oil Red O staining, adipogenic marker gene expression","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined adipogenic phenotype and co-regulated partner identified, single lab","pmids":["30582412"],"is_preprint":false},{"year":2026,"finding":"METTL16 methyltransferase adds m6A modifications to MSMO1 mRNA, stabilizing the transcript via the reader protein IGF2BP2. Elevated MSMO1 disrupts intracellular cholesterol homeostasis, triggering ER stress and activating MAPK-p38/NF-κB signaling by promoting TAK1/TAB complex formation and TAK1 autophosphorylation in colorectal cancer cells.","method":"MeRIP-seq, MeRIP-qPCR, RIP, co-immunoprecipitation, IP-MS, RNA stability assays, RNA-seq, xenograft models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, RIP, Co-IP, IP-MS) establishing m6A writer-reader-target axis, single lab","pmids":["41845506"],"is_preprint":false},{"year":2026,"finding":"MSMO1 regulates the metabolism of 14-demethyllanosterol (T-MAS), and elevated MSMO1 contributes to chemotherapy resistance in breast cancer via the PERK/eIF2α/ATF4/CHOP signaling pathway.","method":"Exosome liquid biopsy transcriptomics, in vitro functional assays, pathway inhibition experiments","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred from correlative and pharmacological data; mechanistic link to PERK pathway is not fully reconstituted, single lab","pmids":["41782822"],"is_preprint":false},{"year":2023,"finding":"miR-19b-3p directly targets MSMO1 mRNA (validated by dual luciferase reporter assay), reducing MSMO1 protein levels. Estrogen directly promotes MSMO1 transcription via estrogen receptor α (ERα) and also upregulates MSMO1 indirectly by suppressing miR-19b-3p. In LMH cells, MSMO1 targeting by miR-19b-3p decreases intracellular cholesterol content.","method":"Dual luciferase reporter assay, Western blot, miRNA overexpression/knockdown, estrogen receptor antagonist treatment, site-directed mutation of ERα binding site","journal":"Poultry science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase validation of direct miRNA-target interaction plus ERα mechanistic dissection, single lab, avian model","pmids":["37939591"],"is_preprint":false},{"year":2025,"finding":"miR-584-5p directly targets MSMO1 mRNA (validated by luciferase reporter assay). MSMO1 overexpression enhances breast cancer cell migration and invasion, and silencing MSMO1 diminishes AKT pathway activity, placing MSMO1 upstream of AKT/PI3K signaling.","method":"Luciferase reporter assay, Western blotting, siRNA knockdown, overexpression, in vivo xenograft","journal":"Protein and peptide letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase validation of miRNA-target interaction and pathway placement by KD, single lab","pmids":["39950465"],"is_preprint":false}],"current_model":"MSMO1 (SC4MOL/ERG25) is an endoplasmic reticulum-resident, membrane-bound, nonheme iron-dependent C-4 sterol methyl oxidase that catalyzes the first step of C-4 methyl group removal in the cholesterol/ergosterol biosynthesis pathway, acting on 4,4-dimethylzymosterol; its protein levels are controlled by MARCHF6-mediated ubiquitination and ERAD-dependent proteasomal degradation in response to cellular sterol levels, while its transcript is regulated by SREBP-2 and m6A modification (deposited by METTL16, read by IGF2BP2); accumulation of its sterol substrates (meiosis-activating/8,9-unsaturated sterols) activates LXR signaling and promotes oligodendrocyte differentiation, and loss of MSMO1 function in humans causes methylsterol accumulation leading to LXR-driven cell overproliferation, immune dysfunction, and a multisystem developmental syndrome."},"narrative":{"mechanistic_narrative":"MSMO1 (SC4MOL/ERG25) is an endoplasmic reticulum-resident, membrane-bound sterol C-4 methyl oxidase that catalyzes the first step in removal of the C-4 methyl groups during cholesterol/ergosterol biosynthesis, acting downstream of lanosterol on 4,4-dimethylzymosterol [PMID:8552601, PMID:9326581]. Functional studies in fungal orthologs establish that the enzyme carries histidine-rich clusters characteristic of nonheme iron membrane oxidases and a C-terminal ER retrieval signal, and that these histidine residues are essential for catalytic activity [PMID:8552601, PMID:10783002, PMID:12546417]. The human enzyme localizes to the ER, removes C4-methylsterols (meiosis-activating sterols), and its loss-of-function causes accumulation of these methylsterols that act as ligands for liver X receptors LXRα/β, driving cell overproliferation and immune dysfunction in a multisystem human syndrome [PMID:8663358, PMID:21285510]. MSMO1 is the most tightly regulated enzyme of the C4-demethylation step: its protein is rapidly turned over by ERAD and MARCHF6-mediated ubiquitination in response to sterol levels, while its transcript is controlled by SREBP-2 and by METTL16/IGF2BP2 m6A modification, and knockdown lowers total cellular cholesterol [PMID:12667960, PMID:32868373, PMID:36958722, PMID:41845506]. Accumulation of its 8,9-unsaturated sterol substrates promotes oligodendrocyte differentiation, and MSMO1 expression modulates adipogenesis and tumor cell behavior through downstream cholesterol-homeostasis and stress-signaling axes [PMID:35128409, PMID:30582412, PMID:39950465].","teleology":[{"year":1996,"claim":"Established the enzymatic identity and catalytic mechanism of the gene by showing the yeast ortholog ERG25 is the C-4 sterol methyl oxidase acting on 4,4-dimethylzymosterol, and that the human homolog exists and is ER-localized.","evidence":"Genetic complementation, disruptant sterol profiling, and sequence analysis in yeast; cloning, mapping, Western, immunofluorescence, and fractionation for the human homolog","pmids":["8552601","8663358"],"confidence":"High","gaps":["Direct demonstration of nonheme iron coordination was inferred from sequence motifs, not measured","The two human protein species (34 and 75 kDa) were not mechanistically resolved","No reconstituted enzymatic assay of the human protein"]},{"year":2002,"claim":"Defined which residues are required for catalysis, confirming the functional importance of the histidine-rich clusters and specific point positions through conditional-lethal alleles.","evidence":"Random mutagenesis generating temperature-sensitive erg25 alleles (e.g. N48D, V133A, F135S) with substrate accumulation readout in Candida and S. cerevisiae","pmids":["10783002","12546417"],"confidence":"Medium","gaps":["Residue-level mapping done in fungal orthologs, not human MSMO1","No structural model of the active site"]},{"year":1997,"claim":"Placed the enzyme at a defined position in the sterol pathway, demonstrating it acts downstream of lanosterol.","evidence":"Genetic epistasis and suppressor analysis with heme/erg11 mutations and sterol profiling in S. cerevisiae","pmids":["9326581"],"confidence":"High","gaps":["Pathway ordering established in yeast","Did not address regulation of the enzyme"]},{"year":2003,"claim":"Identified transcriptional control of the gene by linking its expression to the SREBP-2 sterol-sensing program.","evidence":"RT-PCR, Western, EMSA, SREBP-2 overexpression rescue, and SREBP-catabolism inhibitor in vascular cells","pmids":["12667960"],"confidence":"Medium","gaps":["Direct SREBP-2 binding to the MSMO1 promoter not mapped","Single cell-type context"]},{"year":2011,"claim":"Connected enzyme loss-of-function to human disease and a signaling mechanism, showing accumulated C4-methylsterols act as LXR ligands driving overproliferation and immune dysfunction.","evidence":"Patient mutation identification, biochemical sterol analysis, proliferation and immunocyte functional assays","pmids":["21285510"],"confidence":"High","gaps":["Tissue-specific contributions of LXR activation not fully dissected","Did not address protein-level regulation"]},{"year":2020,"claim":"Revealed post-translational regulation of the enzyme by demonstrating it is an ERAD substrate whose turnover tracks sterol synthesis.","evidence":"Substrate-trapping proteomics, ubiquitination assays, and genetic epistasis with ERAD ubiquitin ligase mutants in yeast","pmids":["32868373"],"confidence":"High","gaps":["Specific ubiquitin ligase identity established in yeast, not human","Degradation signal on the protein not mapped"]},{"year":2021,"claim":"Established a cell-fate consequence of substrate accumulation, showing the enzyme's 8,9-unsaturated sterol substrates promote oligodendrocyte differentiation.","evidence":"Genetic suppression, selective inhibitor (CW4142), exogenous sterol rescue distinguishing saturated vs unsaturated analogs, and in vivo brain sterol profiling","pmids":["35128409"],"confidence":"High","gaps":["Receptor/effector mediating the differentiation response not defined","Link to LXR vs other sterol sensors not resolved"]},{"year":2023,"claim":"Identified the human E3 ligase and reciprocal sterol-dependent protein/transcript regulation, naming MSMO1 the most regulated enzyme of the C4-demethylation complex.","evidence":"siRNA knockdown, sterol manipulation, protein stability and cholesterol assays in human and CHO cells; MARCHF6 identified as the E3 ligase","pmids":["36958722"],"confidence":"High","gaps":["MARCHF6 recognition determinants on MSMO1 not mapped","Interplay between ERAD and MARCHF6 pathways not reconciled"]},{"year":2026,"claim":"Added an RNA-level regulatory layer and a disease-signaling output, showing METTL16/IGF2BP2 m6A modification stabilizes MSMO1 mRNA and that elevated MSMO1 drives ER stress and inflammatory signaling.","evidence":"MeRIP-seq/qPCR, RIP, Co-IP, IP-MS, RNA stability assays, and xenografts in colorectal cancer cells","pmids":["41845506"],"confidence":"Medium","gaps":["Causal chain from MSMO1 elevation to TAK1/TAB activation is correlative in part","Single tumor context"]},{"year":null,"claim":"How MSMO1 substrate accumulation is decoded into distinct downstream outcomes (LXR activation, oligodendrocyte differentiation, ER-stress/MAPK signaling, AKT/PI3K activity) across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking specific sterol species to specific effector pathways","Human active-site structure and direct iron coordination unconfirmed","Tissue-specific regulatory and signaling wiring not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,5,8]}],"complexes":["C4-demethylation complex"],"partners":["MARCHF6","NSDHL","METTL16","IGF2BP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15800","full_name":"Methylsterol monooxygenase 1","aliases":["C-4 methylsterol oxidase","Sterol-C4-methyl oxidase"],"length_aa":293,"mass_kda":35.2,"function":"Catalyzes the three-step monooxygenation required for the demethylation of 4,4-dimethyl and 4alpha-methylsterols, which can be subsequently metabolized to cholesterol (PubMed:21285510, PubMed:23583456, PubMed:26114596, PubMed:28673550, PubMed:36958722). Also involved in drug metabolism, as it can metabolize eldecalcitol (ED-71 or 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)-cholecalciferol), a second-generation vitamin D analog, into 1alpha,2beta,25-trihydroxy vitamin D3; this reaction occurs via enzymatic hydroxylation and spontaneous O-dehydroxypropylation (PubMed:26038696)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q15800/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MSMO1","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MSMO1","total_profiled":1310},"omim":[{"mim_id":"616834","title":"MICROCEPHALY, CONGENITAL CATARACT, AND PSORIASIFORM DERMATITIS; MCCPD","url":"https://www.omim.org/entry/616834"},{"mim_id":"607545","title":"METHYLSTEROL MONOOXYGENASE 1; MSMO1","url":"https://www.omim.org/entry/607545"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":537.9}],"url":"https://www.proteinatlas.org/search/MSMO1"},"hgnc":{"alias_symbol":["DESP4","ERG25"],"prev_symbol":["SC4MOL"]},"alphafold":{"accession":"Q15800","domains":[{"cath_id":"-","chopping":"49-291","consensus_level":"high","plddt":96.4372,"start":49,"end":291}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15800","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15800-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15800-F1-predicted_aligned_error_v6.png","plddt_mean":93.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MSMO1","jax_strain_url":"https://www.jax.org/strain/search?query=MSMO1"},"sequence":{"accession":"Q15800","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15800.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15800/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15800"}},"corpus_meta":[{"pmid":"8552601","id":"PMC_8552601","title":"Cloning and characterization of ERG25, the Saccharomyces cerevisiae gene encoding C-4 sterol methyl oxidase.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8552601","citation_count":137,"is_preprint":false},{"pmid":"21285510","id":"PMC_21285510","title":"Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.","date":"2011","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/21285510","citation_count":88,"is_preprint":false},{"pmid":"8663358","id":"PMC_8663358","title":"Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8663358","citation_count":87,"is_preprint":false},{"pmid":"9326581","id":"PMC_9326581","title":"A yeast sterol auxotroph (erg25) is rescued by addition of azole antifungals and reduced levels of heme.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9326581","citation_count":42,"is_preprint":false},{"pmid":"25107308","id":"PMC_25107308","title":"Two C4-sterol methyl oxidases (Erg25) catalyse ergosterol intermediate demethylation and impact environmental stress adaptation in Aspergillus fumigatus.","date":"2014","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25107308","citation_count":39,"is_preprint":false},{"pmid":"12667960","id":"PMC_12667960","title":"Modulation of ERG25 expression by LDL in vascular cells.","date":"2003","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/12667960","citation_count":27,"is_preprint":false},{"pmid":"30582412","id":"PMC_30582412","title":"RNA-Seq analysis reveals a negative role of MSMO1 with a synergized NSDHL expression during adipogenesis of 3T3-L1.","date":"2018","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30582412","citation_count":23,"is_preprint":false},{"pmid":"10783002","id":"PMC_10783002","title":"Cloning and sequencing of the Candida albicans C-4 sterol methyl oxidase gene (ERG25) and expression of an ERG25 conditional lethal mutation in Saccharomyces cerevisiae.","date":"2000","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/10783002","citation_count":20,"is_preprint":false},{"pmid":"36046654","id":"PMC_36046654","title":"Down-regulation of MSMO1 promotes the development and progression of pancreatic cancer.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36046654","citation_count":19,"is_preprint":false},{"pmid":"36958722","id":"PMC_36958722","title":"Cholesterol synthesis enzyme SC4MOL is fine-tuned by sterols and targeted for degradation by the E3 ligase MARCHF6.","date":"2023","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/36958722","citation_count":18,"is_preprint":false},{"pmid":"33161406","id":"PMC_33161406","title":"New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.","date":"2020","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/33161406","citation_count":14,"is_preprint":false},{"pmid":"37939591","id":"PMC_37939591","title":"miR-19b-3p regulated by estrogen controls lipid synthesis through targeting MSMO1 and ELOVL5 in LMH cells.","date":"2023","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/37939591","citation_count":14,"is_preprint":false},{"pmid":"35399500","id":"PMC_35399500","title":"Erg25 Controls Host-Cholesterol Uptake Mediated by Aus1p-Associated Sterol-Rich Membrane Domains in Candida glabrata.","date":"2022","source":"Frontiers in cell and developmental 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antibiotics","url":"https://pubmed.ncbi.nlm.nih.gov/12546417","citation_count":1,"is_preprint":false},{"pmid":"40451886","id":"PMC_40451886","title":"CRISPR-Cas9 RNP-Mediated Deletion of ERG25 in Non-albicans Candida Species, Including Candida auris.","date":"2025","source":"Medical mycology journal","url":"https://pubmed.ncbi.nlm.nih.gov/40451886","citation_count":0,"is_preprint":false},{"pmid":"41845506","id":"PMC_41845506","title":"METTL16-mediated m6A modification of MSMO1 modulates cholesterol metabolism and activates MAPK-p38/NF-κB signaling in colorectal cancer.","date":"2026","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/41845506","citation_count":0,"is_preprint":false},{"pmid":"41903379","id":"PMC_41903379","title":"Effects of the androstenedione-MSMO1 axis on proliferation, apoptosis, and steroid hormone synthesis and secretion in porcine granulosa cells.","date":"2026","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/41903379","citation_count":0,"is_preprint":false},{"pmid":"41718295","id":"PMC_41718295","title":"Infantile Cataracts Associated with a Homozygous Missense MSMO1 Variant-Case Report and Literature Review.","date":"2026","source":"Reports (MDPI)","url":"https://pubmed.ncbi.nlm.nih.gov/41718295","citation_count":0,"is_preprint":false},{"pmid":"41413001","id":"PMC_41413001","title":"P10 Treatment-refractory psoriasiform dermatitis resulting from a rare genetic alteration in MSMO1 with marked improvement with combined cholesterol and statin use.","date":"2025","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/41413001","citation_count":0,"is_preprint":false},{"pmid":"41782822","id":"PMC_41782822","title":"MSMO1 promotes chemotherapy resistance through modulation of T-MAS metabolism via PERK/elF2α/ATF4/CHOP pathway.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41782822","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.21.25334163","title":"Present-day admixed genomes reveal prehistoric adaptation to cold, maritime diet, and local pathogens in Patagonia","date":"2025-08-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.21.25334163","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16084,"output_tokens":3874,"usd":0.053181,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11718,"output_tokens":3355,"usd":0.071233,"stage2_stop_reason":"end_turn"},"total_usd":0.124414,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"ERG25 (yeast ortholog of MSMO1) encodes a C-4 sterol methyl oxidase that catalyzes the first of three enzymatic steps required to remove the two C-4 methyl groups in sterol biosynthesis. The protein contains a C-terminal ER retrieval signal (KKXX) and three histidine-rich clusters found in eukaryotic membrane desaturases and bacterial alkane hydroxylases, consistent with a nonheme iron-binding mechanism. Disruption of ERG25 leads to accumulation of 4,4-dimethylzymosterol.\",\n      \"method\": \"Genetic complementation, mutagenesis, sterol profile analysis by disruption mutant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional complementation, disruptant sterol profiling, and sequence-based mechanistic annotation replicated across two independent 1996 papers\",\n      \"pmids\": [\"8552601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human homolog of ERG25 (MSMO1/SC4MOL) was cloned, sequenced, and mapped to chromosome 4q32-34. Western analysis showed two proteins of 34 and 75 kDa; both are membrane-bound and contain one N-glycosyl unit. Immunofluorescence localized the proteins to the endoplasmic reticulum and plasma membrane. ERG25 protein levels are regulated by an end product of the ergosterol pathway rather than by iron.\",\n      \"method\": \"Western blot, immunofluorescence, subcellular fractionation, glycosylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (ER/PM), multiple methods (WB, IF, fractionation) in a single lab\",\n      \"pmids\": [\"8663358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A temperature-sensitive point mutation within the histidine-cluster region of Candida albicans Erg25p (ortholog of MSMO1) causes conditional lethality, confirming that the histidine-rich clusters are functionally essential for C-4 sterol methyl oxidase activity.\",\n      \"method\": \"Random mutagenesis, temperature-sensitive allele rescue, sequence analysis\",\n      \"journal\": \"Lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — active-site mutagenesis implication via ts allele, single lab study\",\n      \"pmids\": [\"10783002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Temperature-sensitive erg25 mutations including substitutions N48D, V133A, and F135S cause accumulation of 4,4-dimethylzymosterol at non-permissive temperature, confirming ERG25 is required for C-4 demethylation and that these residues are important for enzyme function.\",\n      \"method\": \"Random mutagenesis, sterol profiling at non-permissive temperature\",\n      \"journal\": \"The Journal of antibiotics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with defined substrate accumulation readout, single lab\",\n      \"pmids\": [\"12546417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Genetic epistasis analysis in S. cerevisiae shows that erg25 auxotrophy can be suppressed by combining erg11 with leaky heme biosynthesis mutations (slu1/slu2, alleles of HEM2 and HEM4), resulting in accumulation of lanosterol which supports growth. This places ERG25 downstream of lanosterol in the ergosterol pathway and demonstrates that lanosterol can substitute for ergosterol under these conditions.\",\n      \"method\": \"Genetic epistasis, suppressor screen, sterol profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple defined mutations, sterol profiling, functionally validated pathway position\",\n      \"pmids\": [\"9326581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss-of-function mutations in human SC4MOL (MSMO1) cause accumulation of C4-methylsterols (meiosis-activating sterols, MASs). These accumulated MASs act as ligands for liver X receptors LXRα and LXRβ, leading to cell overproliferation in skin and blood and substantially altered immunocyte phenotype and in vitro function. This establishes MSMO1 as the enzyme catalyzing C4-methylsterol demethylation in human cholesterol synthesis.\",\n      \"method\": \"Patient mutation identification, biochemical sterol analysis, cell proliferation assays, immunocyte functional assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human loss-of-function with defined biochemical substrate accumulation, LXR ligand mechanism, multiple orthogonal functional readouts\",\n      \"pmids\": [\"21285510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ERG25/SC4MOL expression in vascular endothelial and smooth muscle cells is downregulated by LDL in a time- and dose-dependent manner. This downregulation is mediated through SREBP-2: LDL reduces SREBP-2 mRNA, and overexpression of SREBP-2 blocks LDL-induced ERG25 downregulation. An inhibitor of SREBP catabolism abolishes LDL-induced ERG25 downregulation.\",\n      \"method\": \"RT-PCR, Western blot, EMSA, transient transfection with SREBP-2 overexpression, pharmacological inhibitor\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation mechanism established by multiple methods (RT-PCR, EMSA, overexpression rescue), single lab\",\n      \"pmids\": [\"12667960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Yeast Erg25 (ortholog of MSMO1) is a substrate for ER-associated degradation (ERAD): it is ubiquitinated, associates with stalled proteasomes, and its degradation depends on ERAD-associated ubiquitin ligases. Its turnover is regulated by sterol synthesis levels.\",\n      \"method\": \"Substrate trapping proteomics, affinity isolation, LC-MS/MS, ubiquitination assay, genetic epistasis with ERAD ubiquitin ligase mutants\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (proteomics, ubiquitination, genetic epistasis with ERAD machinery), single lab but rigorous\",\n      \"pmids\": [\"32868373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human SC4MOL (MSMO1) protein is rapidly turned over and is a substrate of the E3 ubiquitin ligase MARCHF6. Sterol depletion stabilizes SC4MOL protein levels, while sterol excess downregulates both SC4MOL transcript and protein. SC4MOL depletion by siRNA causes a significant decrease in total cellular cholesterol, identifying it as the most regulated enzyme in the C4-demethylation complex.\",\n      \"method\": \"siRNA knockdown, sterol manipulation, protein stability assays, cholesterol measurement in cultured mammalian cells (human and CHO)\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MARCHF6 as E3 ligase substrate established with sterol manipulation and KD phenotype, two cell line systems, multiple orthogonal readouts\",\n      \"pmids\": [\"36958722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic suppression of SC4MOL (MSMO1) increases oligodendrocyte formation from progenitor cells. The mechanism involves cellular accumulation of SC4MOL's 8,9-unsaturated sterol substrates, as exogenous addition of purified SC4MOL substrates (but not their 8,9-saturated analogs) promotes oligodendrocyte differentiation. A selective SC4MOL inhibitor (CW4142) induces accumulation of SC4MOL's sterol substrates in mouse brain in vivo.\",\n      \"method\": \"Genetic suppression, small-molecule inhibitors, exogenous sterol addition, in vivo brain sterol profiling\",\n      \"journal\": \"RSC chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological convergent evidence, substrate rescue experiment distinguishes saturated vs unsaturated analogs, in vivo validation\",\n      \"pmids\": [\"35128409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MSMO1 overexpression inhibits 3T3-L1 adipogenesis and downregulates adipogenic marker genes, while MSMO1 knockdown has the opposite effect. MSMO1 and its partner NSDHL show a synergized (co-regulated) expression pattern during adipogenesis.\",\n      \"method\": \"Overexpression, siRNA knockdown, RNA-Seq, Oil Red O staining, adipogenic marker gene expression\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined adipogenic phenotype and co-regulated partner identified, single lab\",\n      \"pmids\": [\"30582412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL16 methyltransferase adds m6A modifications to MSMO1 mRNA, stabilizing the transcript via the reader protein IGF2BP2. Elevated MSMO1 disrupts intracellular cholesterol homeostasis, triggering ER stress and activating MAPK-p38/NF-κB signaling by promoting TAK1/TAB complex formation and TAK1 autophosphorylation in colorectal cancer cells.\",\n      \"method\": \"MeRIP-seq, MeRIP-qPCR, RIP, co-immunoprecipitation, IP-MS, RNA stability assays, RNA-seq, xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, RIP, Co-IP, IP-MS) establishing m6A writer-reader-target axis, single lab\",\n      \"pmids\": [\"41845506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MSMO1 regulates the metabolism of 14-demethyllanosterol (T-MAS), and elevated MSMO1 contributes to chemotherapy resistance in breast cancer via the PERK/eIF2α/ATF4/CHOP signaling pathway.\",\n      \"method\": \"Exosome liquid biopsy transcriptomics, in vitro functional assays, pathway inhibition experiments\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred from correlative and pharmacological data; mechanistic link to PERK pathway is not fully reconstituted, single lab\",\n      \"pmids\": [\"41782822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-19b-3p directly targets MSMO1 mRNA (validated by dual luciferase reporter assay), reducing MSMO1 protein levels. Estrogen directly promotes MSMO1 transcription via estrogen receptor α (ERα) and also upregulates MSMO1 indirectly by suppressing miR-19b-3p. In LMH cells, MSMO1 targeting by miR-19b-3p decreases intracellular cholesterol content.\",\n      \"method\": \"Dual luciferase reporter assay, Western blot, miRNA overexpression/knockdown, estrogen receptor antagonist treatment, site-directed mutation of ERα binding site\",\n      \"journal\": \"Poultry science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase validation of direct miRNA-target interaction plus ERα mechanistic dissection, single lab, avian model\",\n      \"pmids\": [\"37939591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-584-5p directly targets MSMO1 mRNA (validated by luciferase reporter assay). MSMO1 overexpression enhances breast cancer cell migration and invasion, and silencing MSMO1 diminishes AKT pathway activity, placing MSMO1 upstream of AKT/PI3K signaling.\",\n      \"method\": \"Luciferase reporter assay, Western blotting, siRNA knockdown, overexpression, in vivo xenograft\",\n      \"journal\": \"Protein and peptide letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase validation of miRNA-target interaction and pathway placement by KD, single lab\",\n      \"pmids\": [\"39950465\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSMO1 (SC4MOL/ERG25) is an endoplasmic reticulum-resident, membrane-bound, nonheme iron-dependent C-4 sterol methyl oxidase that catalyzes the first step of C-4 methyl group removal in the cholesterol/ergosterol biosynthesis pathway, acting on 4,4-dimethylzymosterol; its protein levels are controlled by MARCHF6-mediated ubiquitination and ERAD-dependent proteasomal degradation in response to cellular sterol levels, while its transcript is regulated by SREBP-2 and m6A modification (deposited by METTL16, read by IGF2BP2); accumulation of its sterol substrates (meiosis-activating/8,9-unsaturated sterols) activates LXR signaling and promotes oligodendrocyte differentiation, and loss of MSMO1 function in humans causes methylsterol accumulation leading to LXR-driven cell overproliferation, immune dysfunction, and a multisystem developmental syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MSMO1 (SC4MOL/ERG25) is an endoplasmic reticulum-resident, membrane-bound sterol C-4 methyl oxidase that catalyzes the first step in removal of the C-4 methyl groups during cholesterol/ergosterol biosynthesis, acting downstream of lanosterol on 4,4-dimethylzymosterol [#0, #4]. Functional studies in fungal orthologs establish that the enzyme carries histidine-rich clusters characteristic of nonheme iron membrane oxidases and a C-terminal ER retrieval signal, and that these histidine residues are essential for catalytic activity [#0, #2, #3]. The human enzyme localizes to the ER, removes C4-methylsterols (meiosis-activating sterols), and its loss-of-function causes accumulation of these methylsterols that act as ligands for liver X receptors LXR\\u03b1/\\u03b2, driving cell overproliferation and immune dysfunction in a multisystem human syndrome [#1, #5]. MSMO1 is the most tightly regulated enzyme of the C4-demethylation step: its protein is rapidly turned over by ERAD and MARCHF6-mediated ubiquitination in response to sterol levels, while its transcript is controlled by SREBP-2 and by METTL16/IGF2BP2 m6A modification, and knockdown lowers total cellular cholesterol [#6, #7, #8, #11]. Accumulation of its 8,9-unsaturated sterol substrates promotes oligodendrocyte differentiation, and MSMO1 expression modulates adipogenesis and tumor cell behavior through downstream cholesterol-homeostasis and stress-signaling axes [#9, #10, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the enzymatic identity and catalytic mechanism of the gene by showing the yeast ortholog ERG25 is the C-4 sterol methyl oxidase acting on 4,4-dimethylzymosterol, and that the human homolog exists and is ER-localized.\",\n      \"evidence\": \"Genetic complementation, disruptant sterol profiling, and sequence analysis in yeast; cloning, mapping, Western, immunofluorescence, and fractionation for the human homolog\",\n      \"pmids\": [\n        \"8552601\",\n        \"8663358\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct demonstration of nonheme iron coordination was inferred from sequence motifs, not measured\",\n        \"The two human protein species (34 and 75 kDa) were not mechanistically resolved\",\n        \"No reconstituted enzymatic assay of the human protein\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined which residues are required for catalysis, confirming the functional importance of the histidine-rich clusters and specific point positions through conditional-lethal alleles.\",\n      \"evidence\": \"Random mutagenesis generating temperature-sensitive erg25 alleles (e.g. N48D, V133A, F135S) with substrate accumulation readout in Candida and S. cerevisiae\",\n      \"pmids\": [\n        \"10783002\",\n        \"12546417\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Residue-level mapping done in fungal orthologs, not human MSMO1\",\n        \"No structural model of the active site\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Placed the enzyme at a defined position in the sterol pathway, demonstrating it acts downstream of lanosterol.\",\n      \"evidence\": \"Genetic epistasis and suppressor analysis with heme/erg11 mutations and sterol profiling in S. cerevisiae\",\n      \"pmids\": [\n        \"9326581\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Pathway ordering established in yeast\",\n        \"Did not address regulation of the enzyme\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified transcriptional control of the gene by linking its expression to the SREBP-2 sterol-sensing program.\",\n      \"evidence\": \"RT-PCR, Western, EMSA, SREBP-2 overexpression rescue, and SREBP-catabolism inhibitor in vascular cells\",\n      \"pmids\": [\n        \"12667960\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct SREBP-2 binding to the MSMO1 promoter not mapped\",\n        \"Single cell-type context\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected enzyme loss-of-function to human disease and a signaling mechanism, showing accumulated C4-methylsterols act as LXR ligands driving overproliferation and immune dysfunction.\",\n      \"evidence\": \"Patient mutation identification, biochemical sterol analysis, proliferation and immunocyte functional assays\",\n      \"pmids\": [\n        \"21285510\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Tissue-specific contributions of LXR activation not fully dissected\",\n        \"Did not address protein-level regulation\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed post-translational regulation of the enzyme by demonstrating it is an ERAD substrate whose turnover tracks sterol synthesis.\",\n      \"evidence\": \"Substrate-trapping proteomics, ubiquitination assays, and genetic epistasis with ERAD ubiquitin ligase mutants in yeast\",\n      \"pmids\": [\n        \"32868373\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific ubiquitin ligase identity established in yeast, not human\",\n        \"Degradation signal on the protein not mapped\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a cell-fate consequence of substrate accumulation, showing the enzyme's 8,9-unsaturated sterol substrates promote oligodendrocyte differentiation.\",\n      \"evidence\": \"Genetic suppression, selective inhibitor (CW4142), exogenous sterol rescue distinguishing saturated vs unsaturated analogs, and in vivo brain sterol profiling\",\n      \"pmids\": [\n        \"35128409\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Receptor/effector mediating the differentiation response not defined\",\n        \"Link to LXR vs other sterol sensors not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the human E3 ligase and reciprocal sterol-dependent protein/transcript regulation, naming MSMO1 the most regulated enzyme of the C4-demethylation complex.\",\n      \"evidence\": \"siRNA knockdown, sterol manipulation, protein stability and cholesterol assays in human and CHO cells; MARCHF6 identified as the E3 ligase\",\n      \"pmids\": [\n        \"36958722\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"MARCHF6 recognition determinants on MSMO1 not mapped\",\n        \"Interplay between ERAD and MARCHF6 pathways not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added an RNA-level regulatory layer and a disease-signaling output, showing METTL16/IGF2BP2 m6A modification stabilizes MSMO1 mRNA and that elevated MSMO1 drives ER stress and inflammatory signaling.\",\n      \"evidence\": \"MeRIP-seq/qPCR, RIP, Co-IP, IP-MS, RNA stability assays, and xenografts in colorectal cancer cells\",\n      \"pmids\": [\n        \"41845506\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal chain from MSMO1 elevation to TAK1/TAB activation is correlative in part\",\n        \"Single tumor context\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MSMO1 substrate accumulation is decoded into distinct downstream outcomes (LXR activation, oligodendrocyte differentiation, ER-stress/MAPK signaling, AKT/PI3K activity) across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unified model linking specific sterol species to specific effector pathways\",\n        \"Human active-site structure and direct iron coordination unconfirmed\",\n        \"Tissue-specific regulatory and signaling wiring not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0016491\",\n        \"supporting_discovery_ids\": [\n          0,\n          3,\n          5\n        ]\n      },\n      {\n        \"term_id\": \"GO:0016787\",\n        \"supporting_discovery_ids\": [\n          0,\n          5\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005783\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1430728\",\n        \"supporting_discovery_ids\": [\n          0,\n          4,\n          5,\n          8\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"C4-demethylation complex\"\n    ],\n    \"partners\": [\n      \"MARCHF6\",\n      \"NSDHL\",\n      \"METTL16\",\n      \"IGF2BP2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}