2. Academic Validation
  3. Persistent activation of TRPM4 triggers necrotic cell death characterized by sodium overload

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

  • Nat Chem Biol. 2025 Aug;21(8):1238-1249. doi: 10.1038/s41589-025-01841-3.
Wan Fu # 1,  Jianghuang Wang # 1,  Tianyu Li # 2 3 4 5,  Yuhui Qiao # 1,  Zili Zhang 1,  Xiaomin Zhang 1,  Mingkai He 1,  Yan Su 1,  Ziye Zhao 1 6,  Chen Li 7,  Ronghua Xiao 8,  Yujun Han 8,  Shen Zhang 1,  Zhiqiang Liu 2 3,  James Lin 7,  Guoqiang Chen 9,  Yang Li 10 11 12 13,  Qing Zhong 14
Affiliations

Affiliations

  • 1 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3 Anesthesia and Brain Function Research Institute, Tongji University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 University of Chinese Academy of Sciences, Beijing, China.
  • 6 Zhiyuan College, Shanghai Jiao Tong University, Shanghai, China.
  • 7 Network and Information Center, Shanghai Jiao Tong University, Shanghai, China.
  • 8 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 9 Hainan Academy of Medical Sciences, School of Basic Medicine and Life Science, Hainan Medical University, Haikou, China.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. liyang@simm.ac.cn.
  • 11 University of Chinese Academy of Sciences, Beijing, China. liyang@simm.ac.cn.
  • 12 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. liyang@simm.ac.cn.
  • 13 National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China. liyang@simm.ac.cn.
  • 14 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. qingzhong@shsmu.edu.cn.
  • # Contributed equally.
PMID: 39915626 DOI: 10.1038/s41589-025-01841-3
Abstract

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.

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