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C1q\/TNF\u2010related protein 6 (<jats:italic>CTRP6<\/jats:italic>) is a member of the <jats:italic>CTRP<\/jats:italic> family analogous to adiponectin and its role in HF pathogenesis remains unclear. Here, we investigated the impact of <jats:italic>CTRP6<\/jats:italic> on HF progression. To mimic heart failure with reduced ejection fraction (HFrEF), we used isoproterenol injection in mice and administered adenovirus vectors expressing <jats:italic>CTRP6<\/jats:italic> (Ad\u2010<jats:italic>CTRP6<\/jats:italic>) via tail vein injection. We assessed cardiac function through echocardiography and histology. <jats:italic>CTRP6<\/jats:italic>'s effects on hypertrophy, fibrosis, apoptosis, oxidative stress and mitochondrial function were analysed. Downstream pathways (phosphorylated AMP\u2010activated protein kinase (p\u2010AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator\u2010activated receptor \u03b3 coactivator 1\u2010\u03b1 (PGC\u20101\u03b1) were studied in heart tissues. In vitro, isoproterenol\u2010stimulated H9c2 cardiomyocytes were treated with <jats:italic>CTRP6<\/jats:italic> to examine viability, apoptosis, F\u2010actin and signalling proteins. Compound C was used to assess AMPK involvement. <jats:italic>CTRP6<\/jats:italic> expression was lower in the plasma of HF patients. In an isoproterenol\u2010induced HFrEF mouse model, adenovirus\u2010mediated overexpression of <jats:italic>CTRP6<\/jats:italic> ameliorated cardiac dysfunction and reduced cardiomyocyte apoptosis, oxidative stress, inflammation and myocardial injury markers. Mechanistically, <jats:italic>CTRP6<\/jats:italic> activation of the AMPK\/SIRT1\/PGC\u20101\u03b1 signalling pathway restored mitochondrial homeostasis, evidenced by reduced mitochondrial reactive oxygen species levels, increased ATP content, and enhanced mitochondrial complex I\/III activities in cardiac tissues. In vitro studies using isoproterenol\u2010stimulated H9c2 cardiomyocytes corroborated these findings, demonstrating that <jats:italic>CTRP6<\/jats:italic> upregulation attenuated hypertrophy, apoptosis, oxidative stress and mitochondrial dysfunction. Furthermore, these effects were partially reversed by the AMPK inhibitor Compound C, implicating the involvement of the AMPK pathway in <jats:italic>CTRP6<\/jats:italic>\u2010mediated cardioprotection. <jats:italic>CTRP6<\/jats:italic> alleviates HF progression through the AMPK\/SIRT1\/PGC\u20101\u03b1 signalling pathway.<\/jats:p>","DOI":"10.1113\/ep092036","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T17:39:27Z","timestamp":1727372367000},"page":"2031-2045","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["CTRP6\u2010mediated cardiac protection in heart failure via the AMPK\/SIRT1\/PGC\u20101\u03b1 signalling pathway"],"prefix":"10.1113","volume":"109","author":[{"given":"Tingting","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital of Anhui Medical University  Hefei Anhui 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