Work

Arsenic exposure provoked prostatic PANoptosis by inducing mitochondrial dysfunction in mice and WPMY-1 cells

Year: 2025

Type: article

Abstract: Inorganic arsenic, a widespread environmental toxicant, significantly contributes to prostate injury . However, the exact cellular mechanisms remain unclear. This study explored the involvement of pyroptosis , apoptosis, and necroptosis (PANoptosis), and their interconnections in arsenic-induced prostate injury. Herein, by employing in vitro (WPMY-1 cells exposed to arsenic for 48 h with or without reactive oxygen species (ROS) and mitochondrial ROS scavenger treatments) and in vivo (C57BL/6 mice were orally gavaged with arsenic and/or N-acetylcysteine for 90 consecutive days) models of arsenic-induced prostate injury and intervention, we demonstrated that sodium arsenite (NaAsO 2 ) triggered mitochondrial damage-activated PANoptosis via the Bax/Bcl-xL/caspase-3/Gasdermin E (GSDME) pathway and the Z-DNA binding protein 1/receptor-interacting protein kinases 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL) signaling pathway . Notably, treatment with NaAsO 2 , GSDME, or MLKL knockdown in WPMY-1 cells increased the phenotype of PANoptosis. Mechanistically, the GSDME-N, GSDMD-N, p-MLKL, and cleaved caspase-3 protein levels were increased (1.4-, 2.67-, 3.51-, and 2.16-fold, respectively) in NaAsO 2 -treated GSDME knockdown WPMY-1 cells, whereas GSDME-N and cleaved caspase-3 protein levels were increased (1.30- and 1.21-fold, respectively) in NaAsO 2 -treated MLKL knockdown WPMY-1 cells. Our study highlights the crucial role of mitochondrial dysfunction in the initiation of PANoptosis during arsenic-induced prostate injury. Furthermore, we provide novel insights into the connections between apoptosis, pyroptosis , and necroptosis , indicating that GSDME and MLKL proteins may act as crucial regulators and potential therapeutic targets for arsenic-induced PANoptosis.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.118139