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Mesencephalic astrocyte\u2010derived neurotrophic factor (MANF), with anti\u2010inflammation and cytoprotection, is found to be negatively correlated with atrial apoptosis and fibrillation. Here, the effect and mechanism of MANF on MH are studied. Myocardial cell\u2010specific MANF knockout (MKO) mice are constructed to establish transverse aortic constriction (TAC) or angiotensin II (Ang II)\u2010induced MH model. MANF is found to be upregulated by MH and protects cardiomyocytes against TAC or Ang II\u2010induced MH. Mechanistically, through single\u2010cell RNA sequencing and metabolomics analysis, MANF in cardiomyocytes is closely involved in glycolysis\u2010oxidative phosphorylation balance and mitochondrial homeostasis. Furthermore, MANF interacts with pro\u2010apoptotic BAX to inhibit BAX mitochondrial translocation, subsequently decreasing mitochondrial damage, cytochrome c release, and cardiomyocyte death. These results indicate a promising clinical value of MANF for MH treatment, and also preliminarily define MANF's role in mitochondrial energy production and mitochondria\u2010associated apoptosis pathway.<\/jats:p>","DOI":"10.1002\/advs.202502835","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T03:53:46Z","timestamp":1753934026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mesencephalic Astrocyte\u2010Derived Neurotrophic Factor Binds BAX to Preserve Mitochondrial Homeostasis and Energy Metabolism for Relieving Myocardial Hypertrophy"],"prefix":"10.1002","volume":"12","author":[{"given":"Dong","family":"Wang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei Anhui 230032 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