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This study investigates the role and mechanism of deubiquitinating enzyme (DUB) ubiquitin\u2010specific protease 20 (USP20) in cardiac hypertrophy. Transcriptomic profiling of hypertrophic hearts shows significant alterations in the expression of DUBs, including a remarkable downregulation of USP20. USP20 is predominantly expressed in cardiomyocytes. Co\u2010immunoprecipitation (Co\u2010IP) followed by liquid chromatography\u2010tandem mass spectrometry (LC\u2010MS\/MS) is used to identify USP20 substrates. Cleavage Under Targets and Tagmentation assay (CUT&amp;Tag) sequencing is employed to identify downstream targets of signal transducer and activator of transcription 3 (STAT3). Functionally, USP20 deficiency exacerbates cardiac hypertrophy induced by either angiotensin II (Ang II) or transverse aortic constriction (TAC), whereas USP20 overexpression alleviates hypertrophic responses. Mechanistically, USP20 deubiquitinates STAT3 by removing K63\u2010linked ubiquitin chains at K177 via its H645 active site, reducing STAT3 phosphorylation and nuclear translocation. This inhibites STAT3's transcriptional activity at coactivator\u2010associated arginine methyltransfer (\n                    <jats:italic>Carm1)<\/jats:italic>\n                    \u00a0promoter, leading to upregulated CARM1 expression and mitigated hypertrophy. Importantly, the STAT3 inhibitor Stattic confirms STAT3 serves as a key substrate mediating the cardiac protective effects of USP20. These findings unveil a novel USP20\/STAT3\/CARM1 axis in cardiomyocytes and reveal its therapeutic potential for cardiac hypertrophy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202416478","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T09:55:32Z","timestamp":1744019732000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cardiomyocyte\u2010Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination"],"prefix":"10.1002","volume":"12","author":[{"given":"Lingfeng","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 310009 China"},{"name":"State Key Laboratory of Transvascular Implantation Devices  Hangzhou 310009 China"},{"name":"Heart Regeneration and Repair Key Laboratory of Zhejiang Province  Hangzhou 310009 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