The E3 Ligase RNF115 Aggravates Pathological Cardiac Hypertrophy via Ubiquitin-Mediated Degradation of SPTBN1

Pathological cardiac hypertrophy represents an adaptive alteration in cardiac structure and function and serves as a critical process in heart failure. Ubiquitination, a classical post-translational modification that regulates protein function and degradation, plays a crucial role in cardiac hypertrophy. In this study, the E3 ubiquitin Ligase ring finger protein 115 (RNF115) is identified as a key pro-hypertrophic factor. RNF115 expression is significantly elevated in heart tissues from patients with heart failure, in mice subjected to transverse aortic constriction (TAC) surgery, and in cardiomyocytes treated with angiotensin II (Ang II). RNF115 knockdown attenuates Ang II-induced cardiomyocyte hypertrophy in vitro, whereas cardiomyocyte-specific RNF115 knockout protects against TAC-induced cardiac hypertrophy and dysfunction in vivo. Mechanistically, upregulation of RNF115 promotes the ubiquitination and degradation of spectrin β, non-erythrocytic 1 (SPTBN1), causing filamentous actin (F-actin) depolymerization, thereby inactivates the Hippo-Yes associated protein (YAP) pathway and drives pro-hypertrophic gene expression. DTD (dithiocarbamate disulfide derivatives) is a potent inhibitor of RNF115 that suppresses SPTBN1 degradation and exerts a protective role in cardiac hypertrophy, indicating that inhibition of RNF115 may represent a potential therapeutic strategy for pathological cardiac hypertrophy and heart failure.