Xia Chen, Xihui Wang, Xiaochun Lei
Pathological cardiac hypertrophy serves as a key contributor to the onset and progression of heart failure, with cardiomyocyte death serving as its key pathological underpinning. Ferroptosis has recently emerged as an important mechanism in cardiac hypertrophy. F-box only protein 10 (FBXO10), a crucial gene in ferroptosis regulation, is implicated in multiple disease contexts. Yet, its role in mediating cardiomyocyte ferroptosis during cardiac hypertrophy remains unexplored. Here, we investigated whether FBXO10 modulates cardiomyocyte ferroptosis and contributes to the progression of cardiac hypertrophy, using HL-1 cardiomyocytes and a transverse aortic constriction (TAC) mouse model. Our data demonstrate that FBXO10 overexpression confers resistance to Erastin-induced ferroptosis in cardiomyocytes, whereas FBXO10 knockdown enhances their susceptibility to ferroptotic cell death. In cellular models of phenylephrine (PE)-induced hypertrophy, cardiomyocyte ferroptosis is observed in conjunction with decreased FBXO10 expression. FBXO10 overexpression suppressed both PE-induced cardiomyocyte ferroptosis and hypertrophy, while FBXO10 silencing exacerbated these effects-a process reversed by ferroptosis inhibition. Mechanistically, FBXO10 interacts with ACSL4, a key promoter of ferroptosis, and facilitates its proteasomal degradation. Overexpression of ACSL4 negated FBXO10's inhibitory role in PE-induced ferroptosis and hypertrophy. In vivo, AAV-mediated cardiomyocyte-specific overexpression of FBXO10 ameliorated TAC-triggered myocardial hypertrophic and fibrotic remodeling, along with reduced myocardial ferroptosis. Collectively, our findings reveal that FBXO10 suppresses pathological cardiac hypertrophy by counteracting ferroptotic cell death in cardiomyocytes via destabilization of ACSL4. This work offers novel molecular mechanisms and promising therapeutic candidates for cardiac hypertrophy intervention.