Activation of Ferroptosis and NF-κB/NLRP3/MAPK Pathways in Methylmercury-Induced Hepatotoxicity.

Abstract

Methylmercury (MeHg) is a potent hepatotoxin with a complex mechanism of inducing liver injury. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is implicated in various toxicological responses, but its role in MeHg-induced liver damage remains under investigation. In this study, we established an acute liver injury (ALI) model in mice via gavage of MeHg (0, 40, 80, 160 μmol/kg). Histopathological analysis revealed dose-dependent liver damage, corroborated by elevated serum biochemical markers, confirming MeHg-induced hepatotoxicity. MeHg exposure raised MDA levels, inhibited SOD and GSH activity, and downregulated CAT expression. Increased iron accumulation and elevated transferrin receptor expression were observed, alongside decreased GPX4 and SLC7A11 levels, indicating ferroptosis involvement. Additionally, inflammation in MeHg-exposed livers was markedly intensified, as evidenced by increased MPO activity, upregulation of pro-inflammatory cytokines, and activation of the NF-κB/NLRP3 signaling pathway. The Keap1/NRF2/HO-1 oxidative stress response pathway was significantly activated, and p38/ERK1/2 MAPK signaling was notably increased. These findings suggested that MeHg induced acute liver injury through the interplay of ferroptosis, oxidative stress, inflammation, and MAPK signaling pathways, providing a scientific basis for future exploration of the mechanisms underlying MeHg-induced hepatotoxicity and potential therapeutic strategies.