Persistent activation of TRPM4 triggers necrotic cell death characterized by sodium overload

被引：5

作者：

Fu, Wan ^{[1
]}

Wang, Jianghuang ^{[1
]}

Li, Tianyu ^{[2
,3
,4
,5
]}

Qiao, Yuhui ^{[1
]}

Zhang, Zili ^{[1
]}

Zhang, Xiaomin ^{[1
]}

He, Mingkai ^{[1
]}

Su, Yan ^{[1
]}

Zhao, Ziye ^{[1
,6
]}

Li, Chen ^{[7
]}

Xiao, Ronghua ^{[8
]}

Han, Yujun ^{[8
]}

Zhang, Shen ^{[1
]}

Liu, Zhiqiang ^{[2
,3
]}

Lin, James ^{[7
]}

Chen, Guoqiang ^{[9
]}

Li, Yang ^{[4
,5
,8
,10
]}

Zhong, Qing ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst Translat Med Cell Fate & Dis, Dept Pathophysiol,Sch Med,Natl Minist Educ,Key Lab, Shanghai, Peoples R China

[2] Tongji Univ, Shanghai Matern & Infant Hosp 1, Sch Med, Shanghai Inst Maternal Fetal Med & Gynecol Oncol,S, Shanghai, Peoples R China

[3] Tongji Univ, Anesthesia & Brain Funct Res Inst, Sch Med, Shanghai, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China

[5] Univ Chinese Acad Sci, Beijing, Peoples R China

[6] Shanghai Jiao Tong Univ, Zhiyuan Coll, Shanghai, Peoples R China

[7] Shanghai Jiao Tong Univ, Network & Informat Ctr, Shanghai, Peoples R China

[8] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China

[9] Hainan Med Univ, Hainan Acad Med Sci, Sch Basic Med & Life Sci, Haikou, Peoples R China

[10] Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai, Peoples R China

来源：

NATURE CHEMICAL BIOLOGY | 2025年 / 21卷 / 08期

基金：

中国国家自然科学基金;

关键词：

NONSELECTIVE CATION CHANNEL; RECEPTOR; CA2+; TRPV1; CLOTRIMAZOLE; MECHANISMS; EXPRESSION; CALCIUM; PORE; ATP;

D O I：

10.1038/s41589-025-01841-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Sodium influx and overload are frequently observed in human tissue injuries. Whether sodium overload imposes a causative effect on necrotic cell death and the mechanism involved are unclear. Here we identify necrocide 1 (NC1) as a compound that induces necrotic cell death through sodium overload, termed NECSO for necrosis by sodium overload. NC1 targets the transient receptor potential cation channel subfamily M member 4 (TRPM4), a nonselective monovalent cation channel, to promote Na+ influx and necrosis. TRPM4-deficient cells are resistant to NC1-induced NECSO. NC1 specifically activates human TRPM4, not mouse TRPM4, because of differences in a transmembrane region, as revealed by domain swapping and molecular docking. Gain-of-function mutations in human TRPM4 linked to cardiac arrhythmias show increased vulnerability to NECSO triggered by NC1 or 2-deoxy-d-glucose. Chemical screening identified NECSO inhibitors that block necrosis induced by NC1 or energy depletion. These findings provide insights into regulated Na+ influx-mediated necrosis and its implications for disease.

引用

页码：1238 / 1249

页数：30

共 63 条

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