Yod1 Mediates Isoproterenolinduced Cardiac Remodeling By Deubiquitinating Pkm2 And Reducing Pkm2 Tetramerization In Cardiomyocytes Qingsong Zheng Yongqiang Xiong Jiachen Xu Jinfu Qian Wu Luo Qinyan Wang Yanni Zhao Yue Luo Yaqian Cui Yi Fang Xiaochen Guo Dingdao Chen Yi Wang Guang Liang by Qing-song Zheng & Yong-qiang Xiong & Jia-chen Xu & Jin-fu Qian & Wu Luo & Qin-yan Wang & Yan-ni Zhao & Yue Luo & Ya-qian Cui & Yi Fang & Xiao-chen Guo & Ding-dao Chen & Yi Wang & Guang Liang instant download after payment.

Heart failure, marked by rising morbidity and mortality rates, poses a significant health challenge. Recent studies suggest thatdeubiquitinating modification of proteins in cardiomyocytes is involved in the development of heart failure. YOD1 is adeubiquitinating enzyme (DUB) implicated in various diseases, including breast cancer, hematological tumors, pancreatic cancer,and vascular endothelial diseases. In this study, we investigated the role of YOD1 in the pathogenesis of cardiac hypertrophy. Micewere administered isoproterenol (ISO, 30 mg·kg−1·d−1, through an osmotic pump) for two weeks to induce heart failure; neonatalmurine ventricular myocytes were exposed to ISO (10 μM) for 24 h for in vitro studies. We showed that YOD1 expression levels weresignificantly upregulated in both in vitro and in vivo cardiac hypertrophy models. In cardiomyocyte-specific Yod1 knockout1234567890();,:(YOD1CKO) mice, ISO-induced cardiac hypertrophy, fibrosis, and dysfunction were significantly ameliorated. We conductedquantitative proteomic screening and identified pyruvate kinase M2 (PKM2) as the substrate of YOD1 in cardiomyocytes. We thendemonstrated that YOD1 directly bound to PKM2 and selectively cleaved K63-linked polyubiquitin chains from PKM2 at theK311 site through its active site H262, which subsequently disintegrated PKM2 tetramers and inhibited mitochondrial oxidativephosphorylation (OXPHOS) in cardiomyocytes. In ISO-treated cardiomyocytes, pretreatment with PKM2 activator TEPP-46 (20 μM)reversed YOD1 overexpression-induced hypertrophy and OXPHOS inhibition. This study reveals a new YOD1-PKM2 axis incardiomyocytes and identifies YOD1 as a potential target for the treatment of ISO-induced cardiac remodeling and heart failure.Keywords: cardiac hypertrophy; cardiomyocytes; isoproterenol; YOD1; PKM2; ubiquitinationActa Pharmacologica Sinica (2025) 0:1–13;