AIM2-PANoptosome-driven PANoptosis in hepatic lipid dysregulation induced by β-HCH and nanoplastics co-exposure.

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.