Xiao Chai Hu Decoction ameliorates doxorubicin-induced cardiotoxicity through an Akkermansia muciniphila–associated gut–heart mechanism

Background Doxorubicin (DOX) induces cardiotoxicity partly through ferroptosis. Xiao Chai Hu Decoction (XCHD) has anti-inflammatory and organ-protective activities, but its effects on DOX-induced cardiac injury and the gut–heart axis remain unclear. Purpose This study investigated whether XCHD attenuates DOX-induced cardiotoxicity through gut microbiota remodeling, with particular emphasis on the contribution of Akkermansia muciniphila and the downstream involvement of BMP10-associated ferroptosis. Methods Male C57BL/6 mice received DOX (5 mg/kg/week for 4 weeks; cumulative dose, 20 mg/kg) and XCHD (5–20 g/kg/day). Cardiac function, myocardial injury, histopathology, iron accumulation, and ferroptosis-related indices were evaluated. Cardiac transcriptomics and fecal 16S rRNA sequencing were combined with antibiotic-mediated microbiota depletion, fecal microbiota transplantation (FMT), and A. muciniphila supplementation to assess microbiota involvement. H9c2 cells treated with XCHD-containing serum and subjected to BMP10 knockdown were used to examine the downstream role of BMP10. Results XCHD improved cardiac function and reduced myocardial injury, fibrosis, iron accumulation, and ferroptosis-associated alterations. Transcriptomic analysis identified BMP10 as a candidate downstream factor suppressed by DOX and restored by XCHD. In H9c2 cells, XCHD-containing serum attenuated ferroptosis-associated changes, whereas BMP10 knockdown weakened these effects, supporting a functional contribution of BMP10 in vitro. XCHD also preserved intestinal barrier integrity, reshaped the gut microbiota, and enriched A. muciniphila . Microbiota depletion abolished the protective effects of XCHD, whereas FMT transferred the protective phenotype. A. muciniphila supplementation reproduced key cardiac and anti-ferroptotic effects, with live bacteria producing greater benefits than heat-inactivated bacteria; these changes were accompanied by restoration of myocardial BMP10 expression. Conclusion XCHD alleviates DOX-induced cardiotoxicity through an A. muciniphila -associated, microbiota-dependent gut–heart mechanism involving intestinal barrier preservation and attenuation of ferroptosis-associated injury. These findings support a “TCM formula–gut microbiota–host response–regulated cell death” framework for XCHD-mediated cardioprotection.