Targeting the Na⁺/K⁺ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity

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.