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The ovarian tumor domain-containing protein 1 (OTUD1) has been implicated in metabolic regulation, but its role in MASLD remains unclear. OTUD1 expression was significantly elevated in liver samples from patients with MASLD and in high-fat diet (HFD)-fed mice, a finding further supported by two independent Gene Expression Omnibus (GEO) cohorts (GSE24807 and GSE126848). Studies using systemic\n                    <jats:italic>Otud1<\/jats:italic>\n                    -knockout mice showed that\n                    <jats:italic>Otud1<\/jats:italic>\n                    deficiency markedly alleviated insulin resistance and inflammation under HFD and high-fat, methionine-restricted, choline-deficient (HFMCD) diet conditions. To assess the hepatocyte-specific and therapeutic relevance of OTUD1,\n                    <jats:italic>Otud1<\/jats:italic>\n                    was silenced in hepatocytes using AAV8-TBG-sh\n                    <jats:italic>Otud1<\/jats:italic>\n                    , which significantly ameliorated HFMCD-induced steatohepatitis. Mechanistically, integrated interactome analyses identified heat shock protein 90\u03b1 (HSP90\u03b1) as a direct substrate of OTUD1. OTUD1 bound to HSP90\u03b1 and removed its K48-linked polyubiquitin chains at K283, thereby preventing its proteasomal degradation and enhancing its stability. This effect was required for OTUD1-driven lipid accumulation in hepatocytes, as the catalytically inactive OTUD1-C320S mutant failed to stabilize HSP90\u03b1 or promote lipid deposition. Transcriptomic profiling further revealed that\n                    <jats:italic>OTUD1<\/jats:italic>\n                    overexpression activated lipid metabolism and inflammatory pathways in OA\/PA-treated LO2 cells. Together, these findings identify OTUD1 as a previously unrecognized driver of MASLD progression through the OTUD1\u2013HSP90\u03b1 axis and suggest that OTUD1 may serve as a potential therapeutic target for metabolic liver disease.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00595-1","type":"journal-article","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T09:07:03Z","timestamp":1789895223000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ovarian tumor domain-containing protein 1 deficiency attenuates metabolic dysfunction-associated steatotic liver disease by promoting the ubiquitination of HSP90\u03b1 in hepatocytes"],"prefix":"10.1186","volume":"7","author":[{"given":"Mei-Qin","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Zhe","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Qin","family":"Ou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Lan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Zhuo","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run-Lei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bai-Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5137-7145","authenticated-orcid":false,"given":"Xiao-Dong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"issue":"1","key":"595_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57585-0","volume":"16","author":"P Lai","year":"2025","unstructured":"Lai P, Miao G, Zhao Y, Han Y, Li Y, Liu Y, et al. 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Written informed consent was obtained from all participants prior to sample collection, in accordance with the Declaration of Helsinki. Liver tissues from patients with steatohepatitis or hepatocellular carcinoma were collected under sterile conditions in accordance with institutional procedures. Animal experiments were approved by the Animal Care and Use Committee of the University of South China (Approval No. 2024017) and were conducted in accordance with the Guidelines of the China Animal Welfare Legislation. 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