Abstract

Doxorubicin (DOX), a widely used chemotherapeutic agent, is clinically limited by DOX-induced heart failure (DIHF). Emerging evidence links gut microbial dysbiosis to exacerbating DIHF progression, yet the mechanisms remain elusive. Herein, we established a rat DIHF susceptibility model to investigate the gut microbiota's regulatory role. Multi-omics analyses indicated that DIHF severity was associated with reduced butyrate-producing bacteria and systemic butyrate levels. Sodium butyrate (NaB) significantly alleviated DOX-induced cardiomyocyte toxicity and DIHF. Mechanistically, NaB strengthened the colonic and cardiac barrier functions and reduced gut microbiota translocation to the heart and cardiac lipopolysaccharide (LPS) accumulation. NaB altered cardiac bacterial composition and functions, reduced cardiac Fe 2+ levels and inhibited cardiomyocyte ferroptosis. Further results confirmed NaB mitigated DOX-induced ferroptosis via the GPX4/GSH pathway. Collectively, this study indicated that butyrate ameliorates DIHF by inhibiting cardiomyocyte ferroptosis through the gut-heart axis, providing translational potential for microbiota-targeted cardioprotective strategy in the DIHF.