Lin Qizhuan, Cai Helei, Yu Fan, Gong Changyong, Wu Yize, Wu Qiufang, Xie Feiqin, Xu Wenhui, Chen Shihua, Yao Xinxin, Jin Libo, Peng Renyi
Institute of Life Sciences & Biomedicine Collaborative Innovation Center of Zhejiang province, College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China.
Apoptosis. 2025 Jul 23. doi: 10.1007/s10495-025-02147-4.
Environmental pollutants pose an increasing threat to human health and ecosystems, with persistent organic pollutants (POPs) and nanoplastics (NPs) drawing significant attention due to their resistance to degradation, high mobility, and bioaccumulation. β-Hexachlorocyclohexane (β-HCH), a typical POP, poses a serious threat to organisms due to its long-term environmental persistence, despite being banned. In this study, we investigated the molecular mechanisms underlying hepatic lipid metabolism disorders induced by combined exposure to β-HCH and NPs using a zebrafish model and Hep G2 cell experiments. Histological staining, RT-qPCR, Western blotting, and immunofluorescence staining demonstrated that β-HCH and NPs co-exposure triggered multiple forms of programmed cell death (PCD), including apoptosis, pyroptosis, and necroptosis, through activation of the pyroptosis, apoptosis and necroptosis (PANoptosis) pathway mediated by the Absent in Melanoma 2 (AIM2)-PANoptosome complex, ultimately leading to lipid metabolism disturbances. RNA interference and gene overexpression experiments further revealed that down or overexpression of AIM2 significantly impacted PANoptosis, confirming the central regulatory role of AIM2 in this process. This study firstly elucidates the regulatory role of the AIM2-PANoptosome complex in the PANoptosis pathway under β-HCH and NPs co-exposure conditions. It provides valuable insights for developing intervention strategies targeting AIM2 for lipid metabolic diseases.
环境污染物对人类健康和生态系统构成了日益严重的威胁，持久性有机污染物（POPs）和纳米塑料（NPs）因其抗降解性、高迁移性和生物累积性而备受关注。β-六氯环己烷（β-HCH）是一种典型的持久性有机污染物，尽管已被禁止，但由于其在环境中的长期持久性，仍对生物体构成严重威胁。在本研究中，我们使用斑马鱼模型和Hep G2细胞实验，研究了β-HCH和NPs联合暴露诱导肝脏脂质代谢紊乱的分子机制。组织学染色、RT-qPCR、蛋白质免疫印迹和免疫荧光染色表明，β-HCH和NPs共同暴露通过激活由黑素瘤缺失2（AIM2）-PANoptosome复合物介导的焦亡、凋亡和坏死性凋亡（PANoptosis）途径，引发了多种形式的程序性细胞死亡（PCD），包括凋亡、焦亡和坏死性凋亡，最终导致脂质代谢紊乱。RNA干扰和基因过表达实验进一步表明，AIM2的下调或过表达显著影响PANoptosis，证实了AIM2在这一过程中的核心调控作用。本研究首次阐明了AIM2-PANoptosome复合物在β-HCH和NPs共同暴露条件下PANoptosis途径中的调控作用。它为开发针对脂质代谢疾病的AIM2干预策略提供了有价值的见解。
