Cardiomyocyte-enriched OTUD5 alleviates pathological myocardial hypertrophy by deubiquitinating STAT3 and modulating the STAT3-PGC-1α axis.

Abstract

Pathological cardiac hypertrophy presents a important public health challenge, particularly in aging populations, highlighting the urgent need for novel therapeutic targets. This study investigates the role and molecular mechanisms of OTUD5 in pathological cardiac hypertrophy. OTUD5 expression is greatly increased in cardiomyocytes from hypertrophic hearts. Deleting cardiomyocyte-specific OTUD5 exacerbates myocardial hypertrophy induced by angiotensin II (Ang II) and transverse aortic constriction (TAC). By contrast, targeted overexpression of OTUD5 in cardiomyocytes alleviates Ang II-induced pathological hypertrophy. Mechanistically, we demonstrate that OTUD5 regulates STAT3 activity by removing the K63-linked ubiquitin chain at lysine 283 (K283) on STAT3 through its C224 residue. This process inhibits both phosphorylation and nuclear translocation of STAT3, effectively relieving its transcriptional repression of PGC1α and enhancing mitochondrial function within cardiomyocytes. Our research uncovers a new OTUD5-STAT3-PGC1α axis that modulates mitochondrial bioenergetics, suggesting it as a potential therapeutic target for pathological cardiac hypertrophy.