2. Academic Validation
  3. MLKL triggers NLRP3 activation in sodium arsenite-induced myocardial necroinflammation

MLKL triggers NLRP3 activation in sodium arsenite-induced myocardial necroinflammation

  • Toxicology. 2025 Aug:515:154132. doi: 10.1016/j.tox.2025.154132.
Yixin Cui 1,  Meng Zhang 2,  Yi Xiao 3,  Jinren Liu 4,  Yonghui Chen 5,  Xingran Ruan 6,  Xu Zhao 7,  Yinan Liu 8,  Yawen Shi 9,  Jing Tian 10,  Lian Li 11,  Xinhe Zhang 12,  Mingzhao Jia 13,  Yi Wang 14,  Xuewei Yang 15,  Zhaoxing Lin 16,  Jinghong Chen 17
Affiliations

Affiliations

  • 1 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: cuiyixin_921@163.com.
  • 2 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: zhang_meng1217@163.com.
  • 3 Shaanxi Provincial Center for Disease Control and Prevention, Xi'an 710054, PR China. Electronic address: 992144707@qq.com.
  • 4 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: liujr_m@163.com.
  • 5 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: cyh287000@163.com.
  • 6 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: ruan_xingran@163.com.
  • 7 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: 2604487177@qq.com.
  • 8 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: liuyinan0821@stu.xjtu.edu.cn.
  • 9 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: sssyw111@stu.xjtu.edu.cn.
  • 10 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: 717278156@qq.com.
  • 11 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: 13209685516@163.com.
  • 12 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: 1404347461@qq.com.
  • 13 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: 2456142511@qq.com.
  • 14 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: yiw_036@163.com.
  • 15 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: 2285187356@qq.com.
  • 16 Shaanxi Provincial Center for Disease Control and Prevention, Xi'an 710054, PR China. Electronic address: 1739423@qq.com.
  • 17 School of Public Health, Xi'an Jiaotong University Health Science Center, NHC Key Laboratory of Environment and Endemic Diseases, National Health Commission of the People's Republic of China, No. 76 Yanta West Road, Xi'an, Shaanxi 710061, PR China. Electronic address: jixiang46@163.com.
PMID: 40188932 DOI: 10.1016/j.tox.2025.154132
Abstract

Prolonged exposure to arsenic elevates the risk of developing a range of cardiovascular disorders. However, the mechanisms underlying myocardial damage from arsenic exposure remain elusive. Our earlier research suggest that drinking arsenic-contaminated water can lead to substantial inflammatory and necrotic injury in the myocardium of rats. This study was to ascertain whether Mixed Lineage Kinase domain-like protein (MLKL) triggers NOD-like Receptor protein-3 (NLRP3) activation during arsenic-induced myocardial necroinflammation in H9C2 cardiomyocytes and Mlkl knockout C57BL/6 mice. We demonstrated that arsenic exposure induces Necroptosis by activating the receptor-interacting serine/threonine-protein kinase-3 (RIPK3)/MLKL pathway in vivo and in vitro. Consistent with our hypotheses, we found that Necroptosis inhibitors (RIPK1 Inhibitor necrostatin-1 [Nec-1], RIPK3 Inhibitor [GSK-872], MLKL inhibitor [NSA]) and Mlkl genetic knockout can partially protect against arsenic-induced inflammatory damage. Additionally, these strategies can downregulate the expression of key proteins associated with the activation of the NLRP3 inflammasome, including NLRP3, Caspase-1, and interleukin-1β (IL-1β). Taken together, our findings demonstrate that MLKL triggers NLRP3 inflammasome activation and plays an essential role in arsenic-induced myocardial necroinflammation.

Keywords

Arsenic; Cardiomyocyte; Myocardium; Necroinflammation; Necroptosis.

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