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Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin\u2010derived peptide ALY688 (ALY688\u2010SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell\u2010derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in\u00a0vitro. High\u2010fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688\u2010SR in\u00a0vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688\u2010SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin\u2010like signaling, including the AMP\u2010activated protein kinase and p38 mitogen\u2010activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688\u2010SR in mice did not influence body weight but significantly ameliorated CDAHF\u2010induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688\u2010SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro\u2010inflammatory and pro\u2010fibrotic genes as demonstrated by transcriptomic analysis. ALY688\u2010SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin\u2010mediated signaling.<\/jats:p>","DOI":"10.1111\/cts.13760","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T11:08:47Z","timestamp":1717758527000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The adiponectin\u2010derived peptide <scp>ALY688<\/scp> protects against the development of metabolic dysfunction\u2010associated steatohepatitis"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4943-3723","authenticated-orcid":false,"given":"Zhe","family":"Huang","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Pharmaceutical Biotechnology The University of Hong Kong  Hong Kong China"},{"name":"Department of Medicine The University of Hong Kong  Hong Kong China"},{"name":"Department of Genetics and 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