FUNDC1-mediated mitochondrial quality control protects against immune checkpoint inhibitor-associated cardiac injury.

Immune checkpoint inhibitors (ICIs) targeting PD-1 are effective cancer therapies but can cause severe myocarditis. The molecular mechanisms linking PD-1 blockade to cardiomyocyte damage are incompletely understood. We established a murine model of anti-PD-1-associated cardiac injury and used human AC16 cardiomyocytes in co-culture with CD8+ T cells. Global Fundc1 knockout (Fundc1-/-) mice and cardiac-specific Fundc1 reconstitution via AAV9 were employed to investigate the role of this mitophagy receptor. Cardiac function was assessed by echocardiography, and injury was evaluated through serum biomarkers, histology, and molecular analyses. Anti-PD-1 treatment induced cardiac dysfunction, myocardial T-cell infiltration, and reduced myocardial FUNDC1 expression in mice. FUNDC1 deficiency, both in vitro and in vivo, aggravated anti-PD-1-associated cardiomyocyte injury, cardiac dysfunction, inflammation, and fibrosis. Conversely, FUNDC1 overexpression or cardiac-specific Fundc1 restoration attenuated these pathological changes. Mechanistically, FUNDC1 loss was associated with altered mitophagy-related marker profiles, mitochondrial protein accumulation, increased oxidative stress, and mitochondrial functional impairment. FUNDC1-mediated mitochondrial quality control may represent an endogenous protective mechanism against anti-PD-1 antibody-associated cardiac injury.