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

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) 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, 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-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-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.