Hepatoprotective effects of the active extracts from Chrysanthemi Indici Flos via regulating epigenetic networks

Chrysanthemi Indici Flos, traditionally known for its heat-clearing, detoxifying, liver-dredging, and vision-improving properties, targets the liver meridian and has a long history of use in China. Our previous study demonstrated that extracts of Chrysanthemi Indici Flos (CIC) exert multiple effects on hepatic disorders, including anti-hepatitis B virus activity and immune modulation, particularly in liver protection. However, the exact mechanism underlying its hepatoprotective effects remains unclear. This study aims to elucidate the hepatoprotective properties of CIC and clarify the mechanisms by which it ameliorates Concanavalin A (Con-A)-induced chronic immune-mediated hepatic damage in mice.CIC administration (7 mg/kg) markedly reduced serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and restored immune homeostasis by lowering the splenic CD4⁺/CD8⁺ T cell ratio. Mechanistically, CIC rebalanced the DNA methylation machinery by downregulating DNA methyltransferase (DNMT1) and upregulating Ten-eleven translocation proteins (TET2) expression, as confirmed by ELISA and qRT-PCR. Methylation capture sequencing further identified eight key epigenetic targets potentially mediating CIC's effects, with enrichment in pathways including Hedgehog signaling, ECM-receptor interaction, Cocaine addiction, and Basal-cell carcinoma. LC-MS-based metabolomic profiling revealed that CIC significantly altered hepatic lipid metabolism and remodeled the immune-metabolic microenvironment. These findings suggest that CIC exerts immunoregulatory and hepatoprotective effects by orchestrating both epigenetic reprogramming and metabolic remodeling. This study offers insights into integrating TCM principles for the establishment of precise treatment programs for complex diseases, and elucidates the scientific connotation of Chrysanthemi Indici Flos's traditional effect for "clearing heat and detoxifying, dredging the liver and targeting the liver meridian".