# Butyrate ameliorates doxorubicin-induced heart failure by inhibiting cardiomyocyte ferroptosis through the gut-heart axis

## TL;DR

Butyrate helps prevent heart failure caused by doxorubicin chemotherapy by reducing heart cell damage through gut-heart interactions.

## Contribution

This study reveals butyrate's novel role in inhibiting cardiomyocyte ferroptosis via the gut-heart axis in doxorubicin-induced heart failure.

## Key findings

- Butyrate reduces gut microbiota translocation to the heart and lowers cardiac lipopolysaccharide accumulation.
- Butyrate inhibits cardiomyocyte ferroptosis through the GPX4/GSH pathway in doxorubicin-treated rats.
- Butyrate strengthens colonic and cardiac barrier functions, altering cardiac bacterial composition.

## 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 Fe2+ levels, and inhibited cardiomyocyte ferroptosis. Further results confirmed that 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 strategies in DIHF.

•Butyrate-producing bacteria and butyrate play a critical role in DIHF susceptibility•We first identified resident bacteria in DOX-treated cardiac tissue•Butyrate lowers cardiac translocation of gut microbiota, alters cardiac bacterial composition•Butyrate inhibits DOX-induced cardiomyocyte ferroptosis via the GPX4/GSH pathway

Butyrate-producing bacteria and butyrate play a critical role in DIHF susceptibility

We first identified resident bacteria in DOX-treated cardiac tissue

Butyrate lowers cardiac translocation of gut microbiota, alters cardiac bacterial composition

Butyrate inhibits DOX-induced cardiomyocyte ferroptosis via the GPX4/GSH pathway

Pharmacology; Microbiome; Metabolomics