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Farnesylation is a post\u2010translational modification critical for cholesterol metabolism and is mediated by the farnesyltransferase beta subunit (FNTB). However, its specific role in cardiomyocyte senescence and cardiac fibrosis remains unclear. Cardiomyocyte\u2010specific\n                    <jats:italic>Fntb<\/jats:italic>\n                    knockout mice were generated to assess cardiac remodeling. RNA sequencing, DNA damage assays, and senescence markers identified molecular pathways. Mechanistic studies included nuclear envelope ultrastructure analysis, laminA assessments. Clinical relevance was assessed via human heart samples from hyperlipidemic patients. In cardiomyocyte\u2010specific\n                    <jats:italic>Fntb<\/jats:italic>\n                    knockout mice, deletion of FNTB induced progressive cardiac fibrosis that preceded hypertrophy development. Pressure overload exacerbated dysfunction in knockouts, revealing fibrosis\u2010dependent vulnerability. Mechanistically, loss of FNTB impaired laminA maturation, destabilized nuclear envelope integrity, and triggered DNA damage response activation, resulting in cardiomyocyte senescence. Senescent cardiomyocytes secreted elevated Tgf\u2010\u03b22 and Gdf15, driving cardiac fibroblast activation. Upstream regulation studies revealed that lipid overload suppressed\n                    <jats:italic>Fntb<\/jats:italic>\n                    transcription via Srebf2 downregulation, recapitulated in hyperlipidemic human hearts showing reduced FNTB expression. Notably, AAV9\u2010mediated\n                    <jats:italic>Fntb<\/jats:italic>\n                    overexpression attenuated cardiac fibrosis in mice fed a high\u2010fat diet. Collectively, our results demonstra that lipid overload suppresses FNTB expression in cardiomyocytes. This deficiency compromises nuclear integrity, triggering a senescence program and driving cardiac fibrosis. These findings uncover a novel mechanism of lipotoxic cardiomyopathy and suggest that farnesylation warrants further investigation as a potential target to fibrotic remodeling in metabolic heart diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202511530","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:48:37Z","timestamp":1772988517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Farnesyltransferase Deficiency in Cardiomyocytes Initiates Senescence and Contributes to Cardiac Fibrosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9875-3523","authenticated-orcid":false,"given":"Yuxiao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 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