Zhang Hao, Cui Jia-Gen, Chen Ming-Shan, Wang Jia-Xin, Sun Xiao-Han, Zhao Yi, Li Jin-Long
College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China.
Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P.R. China.
J Agric Food Chem. 2025 Mar 26;73(12):7432-7444. doi: 10.1021/acs.jafc.4c11022. Epub 2025 Feb 25.
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.
邻苯二甲酸二（2-乙基己基）酯（DEHP）广泛应用于农用塑料中，随着时间的推移，它会通过食物链在人类和动物体内蓄积，从而导致肝脏毒性。最近的研究报告称，细胞焦亡和线粒体损伤与多种肝脏疾病密切相关，但具体机制仍不清楚。为了解决这个问题，建立了体外和体内肝毒性模型。结果表明，接触DEHP会导致肝脏中MEHP的积累，改变肝脏代谢物组成，并引起肝细胞类似细胞焦亡的变化。DEHP处理后，氧化还原稳态失衡，线粒体活性氧（mtROS）过度产生。MEHP暴露激活了由TNF/TNFR1信号介导的细胞焦亡，并上调穿孔蛋白GSDMD-N以破坏肝细胞的线粒体膜。最重要的是，本研究阐明了TNF/TNFR1信号介导的细胞焦亡在线粒体损伤中的潜在作用，并证实调节细胞焦亡有助于维持正常的线粒体功能。
