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  3. Selenium accumulated exposure aggravates the progression of type 2 diabetes mellitus via activating the IRF2/Caspase-4/GSDMD pyroptosis pathway

Selenium accumulated exposure aggravates the progression of type 2 diabetes mellitus via activating the IRF2/Caspase-4/GSDMD pyroptosis pathway

  • J Nutr Biochem. 2026 Jul:153:110326. doi: 10.1016/j.jnutbio.2026.110326.
Lancheng Wei 1,  Zhen Li 1,  Junhao Shan 1,  Xiaolang Chen 2,  Huijiao Zhou 1,  Jin Zhong 1,  Yongmei Yang 1,  Jinfan Chi 1,  Beisiqi Zhang 1,  Hengwei Liang 1,  Zhidong Mo 1,  Linfei Xie 1,  Rui Lin 3,  Yingnan Lv 4,  Shaojun Li 5,  Haiying Zhang 6
Affiliations

Affiliations

  • 1 Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi, China.
  • 2 Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi, China; Department of Molecular Biology, Umeå University, Umeå Sweden.
  • 3 Center for Genomic and Personalized Medicine & Department of Nutrition and Food Hygiene, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
  • 4 Center for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, University Engineering Research Center of Digital Medicine and Healthcare, Guangxi Medical University, Nanning, Guangxi, China. Electronic address: [email protected].
  • 5 Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi, China; School of Public Health, Guangxi Medical University, Nanning, Guangxi, China. Electronic address: [email protected].
  • 6 Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi, China; Department of Public Health, School of Medicine, Guangxi University of Science and Technology, Liuzhou, Guangxi, China. Electronic address: [email protected].
PMID: 41734821 DOI: 10.1016/j.jnutbio.2026.110326
Abstract

Emerging evidence suggests a potential association between high selenium (Se) exposure and the development of type 2 diabetes mellitus (T2DM), a condition often associated with chronic low-grade inflammation. Pyroptosis, a form of programmed cell death characterized by the cleavage and activation of GSDMD by Caspases, has been implicated in T2DM. As an interferon regulatory factor, IRF2 plays a key role in regulating Caspase-GSDMD-mediated Pyroptosis. However, the role of IRF2 in Se-induced islet cell Pyroptosis and its contribution to T2DM development remain unclear. This study investigates the relationship between Se exposure and T2DM, focusing on the molecular mechanisms through which IRF2 mediates Pyroptosis. Our findings show that Se accumulates in the serum of diabetic mice, exacerbating hyperglycemia, reducing serum Insulin levels, and triggering pancreatic tissue atrophy and inflammation. Additionally, Se exposure leads to its accumulation in INS-1 cells, decreasing cell viability and impairing Insulin secretion. Treatment with the Pyroptosis inhibitor disulfiram (DSF) effectively suppressed Se-induced GSDMD expression, GSDMD-N cleavage, and the production of apoptosis-associated speck-like protein (ASC) and interleukins (IL)-18, confirming that Se exposure triggers Pyroptosis in pancreatic islet cells. Both in vivo and in vitro experiments consistently demonstrate that Se exposure induces Pyroptosis through activation of the IRF2/Caspase-4/GSDMD signaling pathway. Notably, lentivirus-mediated silencing of IRF2 significantly suppressed Se-induced Pyroptosis. In conclusion, our study suggests that accumulated Se exposure promotes the progression of T2DM via the IRF2/Caspase-4/GSDMD-mediated Pyroptosis pathway. Moreover, targeting IRF2 expression may effectively alleviate Se-induced pancreatic β-cell damage, providing a promising therapeutic target for the prevention and treatment of T2DM.

Keywords

IRF2; Inflammation; Pyroptosis; Selenium; Type 2 diabetes mellitus.

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