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<p>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<sup>+</sup> 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 <i>TRPM4</i> linked to cardiac arrhythmias show increased vulnerability to NECSO triggered by NC1 or 2-deoxy-<span>d</span>-glucose. Chemical screening identified NECSO inhibitors that block necrosis induced by NC1 or energy depletion. These findings provide insights into regulated Na<sup>+</sup> influx-mediated necrosis and its implications for disease.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年2月6日

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  • Wan Fu,
  • Jianghuang Wang,
  • Tianyu Li,
  • Yuhui Qiao,
  • Zili Zhang,
  • Xiaomin Zhang,
  • Mingkai He,
  • Yan Su,
  • Ziye Zhao,
  • Chen Li,
  • Ronghua Xiao,
  • Yujun Han,
  • Shen Zhang,
  • Zhiqiang Liu,
  • James Lin,
  • Guoqiang Chen,
  • Yang Li,
  • Qing Zhong

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.