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

Authors

Yilin Liu, Yanling Zhou, Xiaole Liang, Jiaohua Chen, Xiufang Li, Sibiao Su

Published in

Biological trace element research. Jun 27, 2026. Epub Jun 27, 2026.

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.

PMID:
42364051
Bibliographic data and abstract were imported from PubMed on 27 Jun 2026.

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