An inulin-based fiber-rich diet alleviates doxorubicin cardiotoxicity via the fMet-KCNE2 axis to attenuate ferroptosis and oxidative stress

Doxorubicin (DOX)-induced cardiotoxicity remains a major complication of Anticancer chemotherapy, and there is a substantial unmet need for safe and effective preventive and therapeutic strategies. This study investigated the potential mechanism of an inulin-based fiber-rich diet (FRD) in preventing DOX-induced cardiomyopathy (DIC). We found that FRD intervention significantly improved the survival of mice with DIC, protected cardiac function, and reduced myocardial injury and histopathological abnormalities. Mechanistically, transcriptomic profiling combined with pathway enrichment analyses indicated that suppression of Ferroptosis constitutes a central component of FRD-mediated cardioprotection. Pharmacological validation further showed that the Ferroptosis inducer erastin abolished the cardioprotective effects of FRD. Targeted metabolomics identified N-formylmethionine (fMet) as a key cardioprotective metabolite that was significantly upregulated following FRD intervention. fMet directly inhibited DOX-induced Ferroptosis in cardiomyocytes, as evidenced by reduced lipid Reactive Oxygen Species (ROS), malondialdehyde (MDA), and intracellular Fe²⁺ levels, together with increased glutathione (GSH) levels and upregulated expression of Glutathione Peroxidase 4 (GPX4) and the cystine/glutamate antiporter (xCT) proteins. Further investigation revealed that the Potassium Channel auxiliary subunit KCNE2 is a critical target of fMet; KCNE2 knockdown abrogated the anti-ferroptotic effects of fMet in cardiomyocytes. Collectively, this study delineates a FRD-fMet-KCNE2 axis that suppresses cardiomyocyte Ferroptosis and mitigates DIC, providing a mechanistic rationale for nutritional interventions to alleviate chemotherapy-associated cardiotoxicity.