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

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

  • J Agric Food Chem. 2026 Mar 18;74(10):8758-8770. doi: 10.1021/acs.jafc.5c15259.
Ranran Zhang 1,  Chengqi Zhang 2,  Yongxian Jia 1,  Jing Lu 1 3,  Shuang Guan 1 3
Affiliations

Affiliations

  • 1 College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
  • 2 Key Laboratory of Special Animal Epidemic Disease, Ministry of Agriculture, Jilin Provincial International Cooperation Key Laboratory for Science and Technology Innovation of Special Animal and Plants, Institute of Special Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
  • 3 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China.
PMID: 41800912 DOI: 10.1021/acs.jafc.5c15259
Abstract

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.

Keywords

GSDMD-N; PANoptosis; benzo[a]pyrene; hepatotoxicity; mitochondrial dysfunction; p-MLKL.

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