Acute liver failure (ALF) induced by poisonous mushrooms represents the most significant threat to humans from mushroom poisoning, primarily attributable to α-amanitin (α-AMA). This study aimed to investigate the mechanism of α-AMA in liver failure. Mice were injected intraperitoneally with α-AMA to induce liver failure in vivo. Liver tissues were stained with H&E, Masson and Sirius Red to assess pathological changes in liver tissue. Human hepatocytes (L02) were cultured with α-AMA. Cell viability and apoptosis were detected by CCK-8 and flow cytometry. Immunohistochemistry, immunofluorescence, qRT-PCR and western blotting were used to detect HMGB1 expression. Co-IP combined with western blot assay was used to detect the level of HMGB1 lactylation in cells. In addition, the levels of inflammatory factors were determined using enzyme-linked immunosorbent assay (ELISA). Compared with the control group, mice induced with α-AMA exhibited significant hepatocyte edema, increased interstitial inflammatory cell infiltration, and elevated fibrosis levels. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were also markedly elevated in α-AMA-treated mice. α-AMA treatment significantly increased hepatic lactate levels and dramatically upregulated HMGB1 expression. Furthermore, in vitro experiments confirmed that α-AMA dose-dependently enhanced both HMGB1 expression and its lactylation level. Critically, α-AMA-induced cellular injury could be effectively reversed by interfering with HMGB1 expression and lactylation. α-AMA elevated the expression of HMGB1 by promoting the lactated modification level of HMGB1, which in turn induced hepatocellular injury and aggravated liver failure.
Huang et al. (Wed,) studied this question.