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Here, the investigation is aimed to determine whether PSFs contribute to cardiac fibrosis and the underlying mechanisms involved. It is observed that premature senescence of fibroblasts is strongly activated in the injured myocardium at 7 days after MI and identified that Kdm4a is located in PSFs\u00a0by the analysis of scRNA\u2010seq data and immunostaining staining. Moreover, fibroblast specific gain\u2010 and loss\u2010of\u2010function assays showed that Kdm4a promoted the premature senescence of fibroblasts and cardiac interstitial fibrosis, contributing to cardiac remodeling in the advanced stage after MI, without influencing early cardiac rupture. ChIP\u2010seq and ChIP\u2010PCR revealed that Kdm4a deficiency promoted autophagy in PSFs\u00a0by reducing Trim44 expression through increased levels of the H3K9me3\u00a0modification in the Trim44 promoter region. Furthermore, a coculture system revealed that Kdm4a overexpression increased the accumulation of PSFs\u00a0and the secretion of senescence\u2010associated secretory phenotype (SASP) factors, subsequently inducing cardiac fibrosis, which could be reversed by Trim44 interference. Kdm4a induces the premature senescence of fibroblasts through Trim44\u2010mediated autophagy and then facilitates interstitial fibrosis after MI, ultimately resulting in cardiac remodeling, but not affecting ventricular rupture.<\/jats:p>","DOI":"10.1002\/advs.202414830","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T07:51:13Z","timestamp":1744703473000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Inhibiting the Histone Demethylase Kdm4a Restrains Cardiac Fibrosis After Myocardial Infarction by Promoting Autophagy in Premature Senescent Fibroblasts"],"prefix":"10.1002","volume":"12","author":[{"given":"Ming","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University  Guangzhou 510515 China"},{"name":"Guangdong Provincial Key Laboratory of Shock and 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