Fang Wenxi, Hu Zhefu, Shen Bo, Zeng Xiaofeng, Chen Si, Wang Shasha, Xie Saiyang, Deng Wei
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, P.R. China.
J Cell Mol Med. 2025 Jun;29(11):e70641. doi: 10.1111/jcmm.70641.
Doxorubicin (DOX) is an anthracycline chemotherapeutic drug used for tumour treatment. Due to DOX-induced cardiotoxicity (DIC), its clinical application has been widely limited. Multiple studies have shown that ferroptosis is involved in the pathogenesis of DIC and that arachidonate 5-lipoxygenase (Alox5) plays an important role in the occurrence and development of ferroptosis. The aim of this study was to provide evidence that silencing Alox5 alleviated DIC by affecting ferroptosis and identify mechanisms. Acute models of DIC were established in wild-type (WT) C57BL/6 and Alox5-deficient (Alox5 KO) mice and neonatal rat ventricular myocytes (NRVMs). Alox5 was upregulated in vivo and in vitro during DIC. Subsequently, we overexpressed the Alox5 gene in adult mice using a recombinant adenovirus expression vector (rAAV9). Compared with that in WT mice, overexpressing Alox5 accelerated DOX-induced myocardial injury and cardiac dysfunction. This finding was also confirmed in vitro. In contrast, silencing the Alox5 gene protected against myocardial injury in the DIC model and reduced ferroptosis and inflammation, and this effect was confirmed in vitro. In addition, transcriptomics and GO enrichment analysis of adult mouse cardiomyocytes showed that Alox5 could ameliorate DIC by inhibiting ferroptosis and inflammation. Moreover, P53 was identified as a target of Alox5. Subsequently, in vivo and in vitro experiments showed that silencing Alox5 could alleviate ferroptosis and inflammation. Further in vivo and in vitro experiments demonstrated that dexrazoxane (DXZ) could ameliorate DIC caused by Alox5 overexpression by alleviating ferroptosis. Mechanistically, silencing Alox5 could reduce reactive oxygen species (ROS) production through the P53/SLC7A11 pathway. Furthermore, P53 inhibitors significantly inhibited the adverse effects of Alox5 overexpression on DIC. The final experiment showed that pharmacological inhibition of Alox5 could prevent DIC in vivo and in vitro. Our study showed that the downregulation of Alox5 alleviated myocardial damage associated with DIC via the P53/SLC7A11 pathway. Therefore, inhibiting Alox5 might be a potential strategy for the treatment of DIC.
多柔比星（DOX）是一种用于肿瘤治疗的蒽环类化疗药物。由于多柔比星诱导的心脏毒性（DIC），其临床应用受到广泛限制。多项研究表明，铁死亡参与了DIC的发病机制，花生四烯酸5-脂氧合酶（Alox5）在铁死亡的发生和发展中起重要作用。本研究的目的是提供证据表明沉默Alox5通过影响铁死亡来减轻DIC，并确定其机制。在野生型（WT）C57BL/6和Alox5缺陷型（Alox5 KO）小鼠以及新生大鼠心室肌细胞（NRVMs）中建立DIC急性模型。在DIC期间，体内和体外的Alox5均上调。随后，我们使用重组腺病毒表达载体（rAAV9）在成年小鼠中过表达Alox5基因。与WT小鼠相比，过表达Alox5加速了多柔比星诱导的心肌损伤和心脏功能障碍。这一发现也在体外得到证实。相反，沉默Alox5基因可在DIC模型中保护心肌免受损伤，并减少铁死亡和炎症，这一效果在体外也得到证实。此外，对成年小鼠心肌细胞的转录组学和GO富集分析表明，Alox5可通过抑制铁死亡和炎症来改善DIC。此外，P53被确定为Alox5的一个靶点。随后，体内和体外实验表明，沉默Alox5可减轻铁死亡和炎症。进一步的体内和体外实验表明，右丙亚胺（DXZ）可通过减轻铁死亡来改善由Alox5过表达引起的DIC。机制上，沉默Alox5可通过P53/SLC7A11途径减少活性氧（ROS）的产生。此外，P53抑制剂显著抑制了Alox5过表达对DIC的不良影响。最终实验表明，对Alox5进行药理抑制可在体内和体外预防DIC。我们的研究表明，Alox5的下调通过P53/SLC7A11途径减轻了与DIC相关的心肌损伤。因此，抑制Alox5可能是治疗DIC的一种潜在策略。
