Arsenic pollution is a global environmental concern. Arsenic-induced chronic liver injury and its irreversible outcomes, including liver cirrhosis and liver cancer, threaten the health of residents in arsenic-contaminated areas. Liver fibrosis is a reversible pathological stage in the progression of arsenic-induced chronic liver injury to cirrhosis and liver cancer. The aim of this study is to identify the epigenetic mechanism of arsenic-induced liver fibrosis based on the dedifferentiation of liver sinusoidal endothelial cells (LSECs). Rats were treated with 0.0, 2.5, 5.0, or 10.0 mg/kg sodium arsenite for 36 weeks. Marked fibrotic phenotypes were observed in the rat livers, manifested by hepatic stellate cell activation and an increased extracellular matrix, as well as the deposition of collagen fibers. The reduced fenestrations on the cells’ surface and the increased expression of the dedifferentiation marker CD31 corroborated the LSECs’ dedifferentiation in the liver tissue, which was also found to be significantly associated with fibrotic phenotypes. We further revealed that arsenic exposure could inhibit the enrichment of histone H3 lysine 18 acetylation (H3K18ac) in the promoters of Fcgr2b and Lyve1, two key genes responsible for maintaining the differentiation phenotype of LSECs. This inhibition subsequently suppressed the genes’ expression, promoting LSEC dedifferentiation and subsequent liver fibrosis. In conclusion, arsenic can trigger liver fibrosis by inhibiting H3K18ac-dependent maintenance of LSEC differentiation. These findings uncover a novel mechanism of arsenic-induced liver fibrosis based on a new insight into epigenetically dependent LSEC dedifferentiation.

Arsenic is a common environmental toxicant. Long-term arsenic exposure can induce various types of liver injury, but the underlying mechanism remains unclear, so effective prevention and treatment measures are unknown. This study aims to explore the mechanism of arsenic-induced rat liver injury based on the histone H3K18 acetylation-dependent antioxidant pathway and to identify the role of a medicinal and edible resource, Rosa roxburghii Tratt juice, in combating it. Hepatic steatosis and inflammatory cell infiltration were observed in rats exposed to different doses of NaAsO₂ using histopathological measurement. Increased 8-OHdG and MDA in liver tissue corroborated hepatic oxidative damage. We further found that a reduction in H3K18ac in the liver showed a dose–response relationship, with an increase in the NaAsO₂ treatment dose, and it was remarkably associated with increased 8-OHdG and MDA. The results of ChIP-qPCR identified that the decreased enrichment of H3K18ac in promoters of the Hspa1a and Hspb8 genes culminated in the inhibition of the genes’ expression, which was found to be involved in the aggravation of hepatic oxidative damage induced by arsenic. Notably, Rosa roxburghii Tratt juice was found to reduce 8-OHdG and MDA in the liver, thereby alleviating the histopathological lesions induced by arsenic, which was modulated by recovering the H3K18ac-dependent transcriptional activation of the Hspa1a and Hspb8 genes. Taken together, we provide a novel epigenetics insight into clarifying the mechanism of arsenic-induced liver injury and its rescue by Rosa roxburghii Tratt juice.