Sun Xingang, Chen Lu, Han Jie, Cai Weixun, Li Shan, Chen Ting, Chen Miao, Zhang Han, He Yuxian, Zheng Liangrong, Wang Lihong
Department of Cardiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
Department of Cardiology and Atrial Fibrillation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Antioxid Redox Signal. 2025 Sep;43(7-9):363-380. doi: 10.1089/ars.2023.0468. Epub 2025 Jun 2.
Doxorubicin (Dox) is a potent chemotherapy agent, yet its clinical use is hampered by cardiotoxicity. Although extensive research has focused on Dox-induced cardiotoxicity (DIC), its mechanism remains elusive. Recent evidence implicates ferroptosis as a key contributor to DIC. The 15-lipoxygenase-1 (ALOX15), involved in lipid peroxidation, is known to play an essential role in ischemia-induced myocardial damage and heart failure; however, its function in DIC is undefined. This study seeks to elucidate the role of ALOX15 in DIC and unravel its underlying mechanism. Both ALOX15 mRNA and protein levels were elevated in DIC models and . Inhibition or silencing of ALOX15 ameliorated lipid peroxidation, ferroptosis, and cardiac dysfunction in Dox-treated mice. Consistently, ALOX15 loss of function protected H9C2 cells against Dox and RSL3-induced toxicity. In addition, we found that linoleic acid increased the susceptibility of H9C2 cells toward Dox-induced damage, which was abolished by ALOX15 inhibition. Furthermore, overexpression aggravated Dox-induced cell damage by aggravating reactive oxygen species (ROS)-mediated ferroptosis. Mechanistically, we discovered that the amelioration of Dox-induced ferroptosis by ALOX15 loss of function occurred through inhibiting the ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathway activation. These results reveal that ALOX15 regulates ferroptosis through ROS-mediated MAPK signaling pathway in DIC, suggesting a potential therapeutic target for DIC intervention. 43, 363-380.
阿霉素（Dox）是一种强效化疗药物，但其临床应用因心脏毒性而受到阻碍。尽管广泛的研究聚焦于阿霉素诱导的心脏毒性（DIC），但其机制仍不清楚。最近的证据表明铁死亡是DIC的关键促成因素。参与脂质过氧化的15-脂氧合酶-1（ALOX15），已知在缺血诱导的心肌损伤和心力衰竭中起重要作用；然而，其在DIC中的功能尚不清楚。本研究旨在阐明ALOX15在DIC中的作用并揭示其潜在机制。在DIC模型中，ALOX15的mRNA和蛋白质水平均升高。抑制或沉默ALOX15可改善阿霉素处理小鼠的脂质过氧化、铁死亡和心脏功能障碍。一致地，ALOX15功能丧失保护H9C2细胞免受阿霉素和RSL3诱导的毒性。此外，我们发现亚油酸增加了H9C2细胞对阿霉素诱导损伤的易感性，而这种易感性可被ALOX15抑制所消除。此外，过表达通过加重活性氧（ROS）介导的铁死亡而加重阿霉素诱导的细胞损伤。从机制上讲，我们发现ALOX15功能丧失对阿霉素诱导的铁死亡的改善是通过抑制ROS介导的丝裂原活化蛋白激酶（MAPK）信号通路激活实现的。这些结果表明，ALOX15在DIC中通过ROS介导的MAPK信号通路调节铁死亡，提示其可能是DIC干预的潜在治疗靶点。43, 363 - 380。
