Integrated network toxicology and transcriptomics uncover that the involvement of NF-κB/NLRP3 pyroptosis axis in mediating BaP-induced hepatotoxicity and fibrosis

Abstract

Benzo[a]pyrene (BaP), a ubiquitous environmental pollutant, exerts hepatotoxicity primarily through its metabolite BPDE. This study combined network toxicology and experimental validation to delineate the mechanisms of BaP-induced liver injury and fibrosis. Network analysis identified ICAM-1 as a potential core target, and previous clinical data confirmed its upregulation in liver injury patients. In a rat model, BaP exposure induced dose-dependent hepatic injury and oxidative stress. Mechanistically, BaP activated the NF-κB/TNF-α signaling axis, upregulating ICAM-1 and initiating NLRP3 inflammasome assembly. Activated NLRP3 promoted Caspase-1-dependent cleavage of GSDMD, leading to hepatocyte pyroptosis and the release of IL-1β and IL-18. Concurrently, ICAM-1 facilitated inflammatory cell infiltration. This sustained inflammatory microenvironment ultimately activated the TGF-β/α-SMA/Col-I axis, driving hepatic stellate cell activation and excessive extracellular matrix deposition, thereby promoting liver fibrosis. Our findings elucidate a cascading pathway linking BaP exposure to oxidative stress, NLRP3-mediated pyroptosis, and hepatic fibrogenesis.