CYLD-mediated DNA damage coordinates pathological cardiac hypertrophy via RIPK1-dependent signaling.

Cardiac remodeling under pressure overload involves maladaptive changes that lead to heart failure. This study investigated the role of the deubiquitinating enzyme CYLD in this process. We found that CYLD expression was significantly upregulated in hypertrophic mouse myocardium and cardiomyocytes. Silencing CYLD markedly attenuated pathological remodeling, improved cardiac function, and reduced DNA damage. Mechanistically, CYLD drives apoptosis by deubiquitinating RIPK1, a key signaling kinase. Inhibition of RIPK1 synergized with CYLD silencing to alleviate hypertrophy-associated DNA damage. Our findings establish the CYLD-RIPK1 axis as a critical regulator of the DNA damage response in cardiac hypertrophy and highlight CYLD inhibition as a promising therapeutic strategy for pressure overload-induced heart failure.