Mitochondrial Targeting of GSDMD-N and p-MLKL Drives PANoptosis in benzo[a]pyrene-Induced Hepatotoxicity.

Benzo[a]pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon (PAH) present in the environment and food chain, causes severe hepatotoxicity. However, the integrated cell death mechanisms underlying BaP-induced liver injury remain poorly defined. Here, we identify PANoptosis, an integrated cell death program encompassing pyroptosis, apoptosis, and necroptosis, as a central mechanism driving BaP-induced liver injury. In vivo and in vitro experiments revealed that BaP activates pyroptosis via the ROS/NLRP3/Caspase-1/GSDMD axis and necroptosis through the ROS/RIPK1/RIPK3/p-MLKL cascade. Remarkably, we uncovered that the pyroptosis executor GSDMD-N and the necroptosis effector p-MLKL translocated from the plasma membrane to mitochondria, inducing mitochondrial outer membrane permeabilization, cytochrome c release, and subsequent caspase-dependent apoptosis. Silencing either GSDMD or MLKL restored mitochondrial integrity and suppressed PANoptosis. Our work expands the conceptual framework of environmental toxicology by revealing how BaP orchestrates integrated cell death through mitochondrial targeting, offering mechanistic insight and potential therapeutic targets for PAH-induced liver injury.