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Homeodomain interacting protein kinase 1 (HIPK1) is a conserved serine\/threonine kinase that can respond to different stress signals, however, whether and how HIPK1 regulates myocardial function is not reported. Here, it is observed that HIPK1 is increased during pathological cardiac hypertrophy. Both genetic ablation and gene therapy targeting HIPK1 are protective against pathological hypertrophy and heart failure in vivo. Hypertrophic stress\u2010induced HIPK1 is present in the nucleus of cardiomyocytes, while HIPK1 inhibition prevents phenylephrine\u2010induced cardiomyocyte hypertrophy through inhibiting cAMP\u2010response element binding protein (CREB) phosphorylation at Ser271 and inactivating CCAAT\/enhancer\u2010binding protein <jats:italic>\u03b2<\/jats:italic> (C\/EBP<jats:italic>\u03b2<\/jats:italic>)\u2010mediated transcription of pathological response genes. Inhibition of HIPK1 and CREB forms a synergistic pathway in preventing pathological cardiac hypertrophy. In conclusion, HIPK1 inhibition may serve as a promising novel therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure.<\/jats:p>","DOI":"10.1002\/advs.202300585","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T10:21:11Z","timestamp":1682504471000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["HIPK1 Inhibition Protects against Pathological Cardiac Hypertrophy by Inhibiting the CREB\u2010C\/EBP<i>\u03b2<\/i> Axis"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2727-7187","authenticated-orcid":false,"given":"Yihua","family":"Bei","sequence":"first","affiliation":[{"name":"Institute of Geriatrics (Shanghai University) Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University  Nantong 226011 China"},{"name":"Cardiac Regeneration and Ageing 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