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

Leng, Bin2,3; Deng, Lin1; Tan, Jianxin4; Lee, Wei-Thye5; Cao, Cheng-Rui1; Wang, Zi-Ping1; Huang, De-Jian2,3; Nie, Xiaowei6; Bian, Jin-Song1,3

2023-08-01

10.1016/j.freeradbiomed.2023.04.008

FREE RADICAL BIOLOGY AND MEDICINE   影响因子和分区

0891-5849

1873-4596

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 DOXinduced 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 NKAa1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAa-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAa1 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 NKAa1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DRregion of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

Na+/K+ ATPase Ferroptosis NKA alpha 1 Doxorubicin Cardiotoxicity

SCI

英语

通讯

National Natural Science Foundation of China (NSFC)[82173800] ; Shenzhen Excellent Science and Technology Innovation Talent Development Programme[RCJC20210706091946002] ; Shenzhen Science and Tech-nology Program[KQTD20200820113040070]

Biochemistry & Molecular Biology ; Endocrinology & Metabolism

Biochemistry & Molecular Biology ; Endocrinology & Metabolism

WOS:000991530200001

ELSEVIER SCIENCE INC

BIOLOGY & BIOCHEMISTRY

Web of Science

1.Southern Univ Sci & Technol, Sch Med, Dept Pharmacol, Shenzhen 518055, Guangdong, Peoples R China
2.Natl Univ Singapore, Dept Food Sci & Technol, 2 Sci Dr 2, Singapore 117542, Singapore
3.Natl Univ Singapore Suzhou Res Inst, 377 Linquan St, Suzhou 215123, Jiangsu, Peoples R China
4.Nanjing Med Univ, Wuxi Peoples Hosp, Lung Transplant Grp, Wuxi 214023, Peoples R China
5.Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore 117600, Singapore
6.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen Key Lab Resp Dis, Shenzhen 518055, Peoples R China

Leng, Bin,Deng, Lin,Tan, Jianxin,et al. Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity[J]. FREE RADICAL BIOLOGY AND MEDICINE,2023,204.

Leng, Bin.,Deng, Lin.,Tan, Jianxin.,Lee, Wei-Thye.,Cao, Cheng-Rui.,...&Bian, Jin-Song.(2023).Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.FREE RADICAL BIOLOGY AND MEDICINE,204.

Leng, Bin,et al."Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity".FREE RADICAL BIOLOGY AND MEDICINE 204(2023).