FMO2 expression confers cardioprotection in doxorubicin therapy while preserving antitumor activity

Background

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.

Methods

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.

Results

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.

Conclusions

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.