Department of Food Science and Technology, National University of Singapore, 2 Science Drive 2, Singapore, 117542, Singapore; National University of Singapore (Suzhou) Research Institute, 377 Linquan Street, Suzhou, 215123, Jiangsu, China.
Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
Free Radic Biol Med. 2023 Aug 1;204:38-53. doi: 10.1016/j.freeradbiomed.2023.04.008. Epub 2023 Apr 24.
Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.
阿霉素（DOX）是一种用于多种癌症的有效化疗药物。然而，其心脏毒性副作用限制了它在临床应用中的使用，铁死亡是 DOX 诱导的心脏毒性（DIC）的关键病理机制。Na+/K+ATP 酶（NKA）活性的降低与 DIC 的进展密切相关。然而，NKA 功能异常是否参与 DOX 诱导的心脏毒性和铁死亡尚不清楚。本研究旨在解析 NKA 功能障碍在 DOX 诱导的铁死亡中的细胞和分子机制，并探讨 NKA 作为 DIC 的潜在治疗靶点。NKAα1 杂合不足小鼠中 NKA 活性降低进一步加重了 DOX 触发的心脏功能障碍和铁死亡。相反，NKAα 亚基的 DR 区抗体（DR-Ab）减轻了 DOX 诱导的心脏功能障碍和铁死亡。在机制上，NKAα1 与 SLC7A11 相互作用形成一种新型蛋白复合物，该复合物直接参与 DIC 的疾病进展。此外，DR-Ab 通过促进 NKAα1/SLC7A11 复合物的结合和维持 SLC7A11 在细胞表面的稳定性来减轻 DIC，从而发挥对 DIC 的治疗作用。这些结果表明，针对 NKA 的 DR 区的抗体可能成为减轻 DOX 诱导的心脏毒性的一种新的治疗策略。
