FMO2 expression confers cardioprotection in doxorubicin therapy while preserving antitumor activity

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent, but its clinical application is limited by severe side effects, particularly DOX-induced cardiomyopathy (DIC) which is closely associated with oxidative stress, DNA damage and, subsequent apoptosis. Flavin-containing monooxygenase 2 (FMO2), a cardiac-enriched enzyme, catalyzes NADPH-dependent oxidative metabolism of diverse pharmaceuticals. Our previous work demonstrated that FMO2 expression confers cardioprotective effects against ischemic cardiomyopathy; however, the role of FMO2 in DIC has not been demonstrated.

DIC was induced in wild-type, FMO2^-/-, and cardiomyocyte-specific FMO2-overexpressing mice. Neonatal rat ventricular myocytes were assessed following adenoviral-mediated FMO2 knockdown or overexpression. Transcriptome profiling and chromatin analysis elucidated the mechanism involving FMO2-mediated attenuation of DOX-induced DNA damage. A xenograft model was used to evaluate the impact of FMO2 on DOX's antitumor efficacy.

FMO2 expression was suppressed in heart following DIC. Genetic ablation of FMO2 exacerbated DIC, whereas cardiomyocyte-specific FMO2 overexpression mitigated DOX-induced cardiac injury. Mechanistically, FMO2 reduced DOX-induced DNA damage by stabilizing chromatin-associated X-ray repair cross-complementing protein 4-like factor (XLF), thereby promoting DNA repair. Furthermore, FMO2 expression did not compromise DOX's antitumor efficacy.

FMO2 expression confers cardiac protection against DIC by stabilizing chromatin-associated XLF to facilitate DNA repair. Critically, cardiac FMO2 expression preserves DOX's antitumor efficacy, establishing it as a potential target for DIC management.