{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:01:14Z","timestamp":1790776874700,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,27]]},"group-title":"Genetics","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01DK139288"],"award-info":[{"award-number":["R01DK139288"]}]},{"name":"National Institutes of Health","award":["5R35GM144103"],"award-info":[{"award-number":["5R35GM144103"]}]},{"name":"National Institutes of Health","award":["K08DK149008-01"],"award-info":[{"award-number":["K08DK149008-01"]}]},{"name":"USF Health Graduate Medical Education Research Grant Program awards","award":["2025-2026"],"award-info":[{"award-number":["2025-2026"]}]},{"name":"USF Health Graduate Medical Education Research Grant Program awards","award":["2026-2027"],"award-info":[{"award-number":["2026-2027"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD\/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD\/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (\n                  <jats:italic>OPA1<\/jats:italic>\n                  ).\n                  <jats:italic>OPA1<\/jats:italic>\n                  transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific\n                  <jats:italic>OPA1<\/jats:italic>\n                  loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify\n                  <jats:italic>OPA1<\/jats:italic>\n                  as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.\n                <\/jats:p>","DOI":"10.64898\/2026.09.24.753666","type":"posted-content","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:00:12Z","timestamp":1790503212000},"source":"Crossref","is-referenced-by-count":0,"title":["OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-0101","authenticated-orcid":false,"given":"Xinting","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of South Florida, Tampa, 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