阿霉素广泛用于治疗恶性肿瘤，但阿霉素引起的心脏毒性严重限制了其临床应用。 Spexin 是一种神经肽，可作为心血管疾病的新型生物标志物。然而，Spexin对阿霉素诱导的心脏毒性的影响尚不清楚。我们建立了阿霉素诱导的体内和体外心脏毒性模型。通过心功能评估、血清心肌肌钙蛋白T和CKMB水平测定以及组织学检查来评估小鼠心脏损伤水平。 CCK8 和 PI 染色用于评估体外心肌细胞培养物中阿霉素诱导的毒性。使用铁橙染色、测定 MDA 和 4-HNE 含量以及铁死亡相关蛋白 SLC7A11 和 GPX4 来评估铁死亡。分别使用 TMRE 和 C11-BODIPY 581/591 探针测量线粒体膜电位和脂质过氧化水平。通过 P62 和 Beclin1 的表达评估心肌自噬。Spexin 治疗改善了阿霉素诱导的心脏毒性小鼠的心功能，并通过减少铁积累、异常脂质代谢和抑制铁死亡来减轻阿霉素诱导的心脏毒性。有趣的是，多柔比星会导致培养的心肌细胞过度自噬，这可以通过 spexin 治疗来缓解。 Beclin 1 的敲除消除了 spexin 对 DIC 小鼠的保护作用。Spexin 通过抑制过度自噬诱导的铁死亡来改善阿霉素诱导的心脏毒性，表明 spexin 可能是对抗阿霉素诱导的心脏毒性的候选药物。 Beclin 1 可能在介导 spexin 对阿霉素诱导的心脏毒性的保护作用中发挥关键作用。© 2024 英国药理学会。

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.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.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.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.© 2024 British Pharmacological Society.