Tremella fuciformis polysaccharides protect against doxorubicin-induced cardiotoxicity via antioxidant and gut microbiota

Background: Cardiotoxicity induced by doxorubicin (Dox) is a major limitation of anthracycline chemotherapy, leading to oxidative stress, mitochondrial dysfunction, and heart failure. Natural polysaccharides with antioxidative and cardioprotective properties have attracted attention as potential therapeutic agents. Methods: In this study, we investigated the protective effects of a polysaccharide from Tremella fuciformis polysaccharide (TFP) in a Dox-induced mouse model of cardiomyopathy and explored the underlying mechanisms. Results: TFP was characterized as a heteropolysaccharide primarily composed of glucose, mannose, and galacturonic acid, with a predominant low-molecular-weight fraction (~1.6 kDa). TFP pretreatment significantly improved cardiac function in Dox-treated mice, as indicated by increased ejection fraction and fractional shortening, and attenuated myocardial fibrosis and serum markers of cardiac injury. Histological and ultrastructural analyses showed that TFP preserved myocardial architecture and mitochondrial integrity. Mechanistically, TFP enhanced antioxidant defenses (SOD, GSH-PX), reduced lipid peroxidation (MDA), and restored ATP production, alleviating oxidative stress and mitochondrial dysfunction. Moreover, 16S rRNA gene sequencing revealed that TFP ameliorated Dox-induced gut microbiota dysbiosis by increasing microbial diversity and reshaping the community structure, including reduced abundance of Escherichia-Shigella and restoration of beneficial taxa such as norank_f__Muribaculaceae and Ligilactobacillus. These microbial changes were significantly correlated with cardiac function and oxidative stress indices. Conclusions: Collectively, TFP mitigates Dox-induced cardiac injury by reducing oxidative stress, preserving mitochondrial bioenergetics, and modulating gut microbiota, highlighting its potential as a natural intervention against anthracycline-associated cardiotoxicity.