Spexin inhibits excessive autophagy‐induced ferroptosis to alleviate doxorubicin‐induced cardiotoxicity by upregulating Beclin 1

Background and Purpose Doxorubicin is widely used in the treatment of malignant tumours, but doxorubicin‐induced cardiotoxicity severely limits its clinical application. Spexin is a neuropeptide that acts as a novel biomarker in cardiovascular disease. However, the effects of spexin on doxorubicin‐induced cardiotoxicity is unclear. Experimental Approach We established a model of doxorubicin‐induced cardiotoxicity both in vivo and in vitro. Levels of cardiac damage in mice was assessed through cardiac function assessment, determination of serum cardiac troponin T and CKMB levels and histological examination. CCK8 and PI staining were used to assess the doxorubicin‐induced toxicity in cultures of cardiomyocytes in vitro. Ferroptosis was assessed using FerroOrange staining, determination of MDA and 4‐HNE content and ferroptosis‐associated proteins SLC7A11 and GPX4. Mitochondrial membrane potential and lipid peroxidation levels were measured using TMRE and C11‐BODIPY 581/591 probes, respectively. Myocardial autophagy was assessed by expression of P62 and Beclin1. Key Results Spexin treatment improved heart function of mice with doxorubicin‐induced cardiotoxicity, and attenuated doxorubicin‐induced cardiotoxicity by decreasing iron accumulation, abnormal lipid metabolism and inhibiting ferroptosis. Interestingly, doxorubicin caused excessive autophagy in cardiomyocyte in culture, which could be alleviated by treatment with spexin. Knockdown of Beclin 1 eliminated the protective effects of spexin in mice with DIC. Conclusion and Implications Spexin ameliorated doxorubicin‐induced cardiotoxicity by inhibiting excessive autophagy‐induced ferroptosis, suggesting that spexin could be a drug candidate against doxorubicin‐induced cardiotoxicity. Beclin 1 might be critical in mediating the protective effect of spexin against doxorubicin‐induced cardiotoxicity. Spexin mitigated Dox‐induced cardiotoxicity by inhibiting excessive autophagy‐induced ferroptosis and upregulating Beclin 1. Image created with Biorender.com, with permission.