2. Academic Validation
  3. TNF/TNFR1 Signaling Mediates DEHP-Induced Hepatocyte Pyroptosis via the GSDMD-mtROS Axis

TNF/TNFR1 Signaling Mediates DEHP-Induced Hepatocyte Pyroptosis via the GSDMD-mtROS Axis

  • J Agric Food Chem. 2025 Mar 26;73(12):7432-7444. doi: 10.1021/acs.jafc.4c11022.
Hao Zhang 1,  Jia-Gen Cui 1,  Ming-Shan Chen 1,  Jia-Xin Wang 1,  Xiao-Han Sun 1,  Yi Zhao 1 2 3,  Jin-Long Li 1 2
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China.
  • 2 Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P.R. China.
  • 3 Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, P.R. China.
PMID: 39999303 DOI: 10.1021/acs.jafc.4c11022
Abstract

Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and Animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that Pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial Reactive Oxygen Species (mtROS) were overproduced. MEHP exposure activates Pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated Pyroptosis in mitochondrial damage and confirms that the regulation of Pyroptosis is helpful in maintaining normal mitochondrial function.

Keywords

Di(2-ethylhexyl) phthalate; Metabolic disorder; Mitochondrial damage; Pyroptosis; TNF/TNFR1 signaling.

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