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

  • Free Radic Biol Med. 2023 Apr 24;S0891-5849(23)00378-7. doi: 10.1016/j.freeradbiomed.2023.04.008.
Bin Leng  1 ,  Lin Deng  2 ,  Jianxin Tan  3 ,  Wei-Thye Lee  4 ,  Cheng-Rui Cao  2 ,  Zi-Ping Wang  2 ,  De-Jian Huang  5 ,  Xiao-Wei Nie  6 ,  Jin-Song Bian  7
Affiliations
  • 1. 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.
  • 2. Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
  • 3. Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China.
  • 4. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
  • 5. 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. Electronic address: [email protected].
  • 6. Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518055, China. Electronic address: [email protected].
  • 7. Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China; National University of Singapore (Suzhou) Research Institute, 377 Linquan Street, Suzhou, 215123, Jiangsu, China. Electronic address: [email protected].
PMID: 37100355 DOI: 10.1016/j.freeradbiomed.2023.04.008
Abstract

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.

Keywords
Cardiotoxicity; Doxorubicin; Ferroptosis; NKAα1; Na(+)/K(+) ATPase; SLC7A11.
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