Doxorubicin (DOX) is an antineoplastic agent that is widely employed in carcinomas, but it can cause cardiotoxicity in clinic. TRIM25 has E3 ubiquitin ligase activities and can ubiquitinate its target proteins. The role of TRIM25 in DOX-induced cardiotoxicity remains unknown. In this study, our results showed that DOX induced pyroptosis of H9c2 cells by TUNEL staining and Western blot assay. Interestingly, TRIM25 was downregulated in DOX-treated H9c2 cells in a time- and dose-dependent manner. TRIM25 attenuated DOX-induced pyroptosis of H9c2 cells. Furthermore, in vitro ubiquitination assay proved that TRIM25 decreased the stability of NLRP1 via promoting the ubiquitination of NLRP1. The rescue experiments confirmed that TRIM25 inhibited DOX-induced H9c2 cells pyroptosis by regulating NLRP1 stability. Animal experiments demonstrated that overexpression of TRIM25 attenuated DOX-induced cardiomyocyte pyroptosis in rats. In summary, TRIM25 exerts its cardioprotective effects by promoting the ubiquitination of NLRP1 in DOX-induced cardiomyocyte pyroptosis, which provides a novel therapeutic strategy for DOX-induced cardiotoxicity.

多柔比星（DOX）是一种广泛用于癌症的抗肿瘤药物，但在临床上可引起心脏毒性。TRIM25 具有 E3 泛素连接酶活性，可以泛素化其靶蛋白。TRIM25 在 DOX 诱导的心脏毒性中的作用仍然未知。在本研究中，我们的结果显示 DOX 通过 TUNEL 染色和蛋白质印迹法诱导 H9c2 细胞发生焦亡。有趣的是，TRIM25 在 DOX 处理的 H9c2 细胞中以时间和剂量依赖性方式下调。TRIM25 减弱 DOX 诱导的 H9c2 细胞焦亡。此外，体外泛素化试验证明TRIM25通过促进NLRP1的泛素化降低了NLRP1的稳定性。救援实验证实，TRIM25 通过调节 NLRP1 稳定性来抑制 DOX 诱导的 H9c2 细胞焦亡。动物实验表明，TRIM25 的过表达减弱了 DOX 诱导的大鼠心肌细胞焦亡。总之，TRIM25 通过促进 NLRP1 在 DOX 诱导的心肌细胞焦亡中的泛素化发挥其心脏保护作用，这为 DOX 诱导的心脏毒性提供了一种新的治疗策略。