Role of H3K18 Acetylation in Cadmium-Associated Modulation of the Nrf2-Keap1/NF-κB Axis and Liver Fibrosis Progression.

Abstract

This study explores how chronic cadmium exposure induces H3K18 acetylation in hepatocytes, regulating the Nrf2-Keap1/NF-κB signaling pathway and promoting liver fibrosis. A CdCl₂-induced mouse model of liver fibrosis and hepatocyte injury was established. The H3K18 acetylation inhibitor DCH36_06 was applied in combination with this model. Various assays were used to assess hepatocyte apoptosis and the expression of H3K18ac, Bax, Nrf2, Keap1, and NF-κB both in vivo and in vitro. Mice were provided with drinking water containing CdCl₂ at a final concentration of 1 g/L. Histological analysis of liver tissues using H&E and Masson staining showed mild fibrosis (G1S1) after 4 weeks and marked cirrhosis (G3S3-4) after 24 weeks. Immunohistochemistry and fluorescence analysis revealed elevated H3K18ac and Bax expression in hepatocytes following cadmium exposure. In vitro, cadmium increased intracellular and ROS accumulation, upregulated endoplasmic reticulum stress-related genes (Perk and Manf), and accelerated apoptosis. Western blotting confirmed increased expression of apoptosis-related proteins Caspase3, Bax, Bcl-2, and HO-1. Under low-dose cadmium exposure, sustained H3K18ac expression in hepatocytes activated the oxidative stress-related Nrf2-Keap1/NF-κB pathway, leading to high levels of Nrf2, Keap1, and NF-κB proteins. Treatment with DCH36_06 reduced ROS accumulation and apoptosis, and downregulated Perk and Manf expression. In the CdCl₂ + DCH36_06 mouse model, fibrosis progression was noticeably slower, indicating that inhibition of H3K18 acetylation mitigates liver damage. Low-dose cadmium exposure promotes H3K18 acetylation in hepatocytes, leading to ROS accumulation and modulation of the Nrf2-Keap1/NF-κB signaling pathways. This cascade triggers oxidative stress and apoptosis, driving the development and progression of liver fibrosis.