AP39 Alleviates HHCY-Induced Myocardial Remodeling by Regulating FUNDC1-Mediated Mitochondrial Dynamics via S-Sulfhydration of NEDD8/CUL4B

Ya Ling Li¹Jianghe Jiang¹chenlong luo¹Yan Shi²Ting Yang²Shengquan Liu¹Chun Chu²Jun Yang^1*

• ¹First Affiliated Hospital of University of South China, Hengyang, China
• ²The Second Affiliated Hospital of the University of South China, Hengyang, China

Hyperhomocysteinemia (HHCY) is a well-recognized risk factor for cardiovascular diseases, however, the molecular mechanisms by which it induces myocardial remodeling remain unclear. Through integrated clinical observations, animal models, and cellular experiments, we demonstrate that HHCY promotes myocardial remodeling by disrupting mitochondrial dynamics and accelerating cardiomyocyte senescence, while also identifying the protective role of AP39, a mitochondria-targeted hydrogen sulfide (H₂S) donor. Retrospective clinical analysis shows that HHCY is significantly associated with left ventricular hypertrophy in hypertensive patients, and elevated homocysteine (HCY) levels increase the risk of ventricular hypertrophy. In animal experiments, HHCY levels exhibited decreased cardiac function (reduced LVFS and increased LVESD), myocardial fibrosis (upregulated α-SMA and Collagen III), and cellular senescence (increased P53 and P16), whereas AP39 intervention significantly ameliorated these pathological changes. Mechanistically, AP39-derived H₂S promotes S-sulfhydration NEDD8/CUL4B complex, and thereby reduces the ubiquitin-dependent degradation of FUNDC1. The resulting upregulation of FUNDC1 restores mitochondrial dynamic homeostasis by weakening its interaction with DRP1, ultimately suppressing cardiomyocyte senescence and ameliorating myocardial remodeling. In summary, our findings uncover a previously unrecognized mechanism whereby AP39 regulates the FUNDC1-DRP1 axis through NEDD8/CUL4B-dependent S-sulfhydration, thereby preserving mitochondrial homeostasis. This study identifies a novel therapeutic target and provides mechanistic insight into HHCY-associated myocardial remodeling.