Sibiao Su

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.

Liver cancer ranks as the fourth most common malignant tumor and the second leading cause of cancer deaths in China. Guangxi is a high-risk region, with a crude incidence rate of 41.65/10⁵, significantly exceeding the national average. At a regional scale, liver cancer incidence in Guangxi exhibits a distinct zonal distribution, which shows notable spatial coupling with cadmium (Cd) concentrations in rice grains, though the underlying mechanism remains unclear. This study systematically investigated this relationship by collecting hepatocellular carcinoma incidence and rice grain Cd data from 44 counties/cities, analyzing blood Cd levels in 105 patients and 105 healthy controls, and comparing paired blood (n = 316) and rice samples (n = 216) from five typical areas. Results demonstrated a significant spatial coupling and correlation between rice Cd distribution and liver cancer incidence. Liver cancer patients had elevated blood Cd levels. High consistency between blood Cd and rice grain Cd levels identified rice consumption as the primary exposure pathway. This study suggests a link between rice cadmium levels and liver cancer in Guangxi, potentially contributing to its geographical distribution. This provincial-scale study provides fundamental data for understanding the chronic hepatocarcinogenic effects of Cd exposure via rice. Graphical Abstract