Geniposide alleviates CCl₄-induced liver fibrosis: Potential involvement of the PERK-CHOP signaling pathway

Geniposide is the primary active component of the cycloether terpenoid glycoside class extracted from the traditional Chinese medicinal herb Gardenia jasminoides, and it possesses multiple pharmacological activities, including neuroprotection, antidiabetic effects and hepatoprotection. It has been shown that endoplasmic reticulum (ER) stress and the apoptosis it mediates play a key role in the progression of liver fibrosis, with the PERK-CHOP signaling pathway serving as a central mechanism regulating hepatic stellate cell (HSC) activation and hepatocyte damage. The present study aimed to investigate whether geniposide alleviates carbon tetrachloride (CCl₄)-induced liver fibrosis in mice associated with reduced ER stress mediated by the protein kinase R-like ER kinase (PERK)- C/EBP homologous protein (CHOP) pathway. A mouse model of liver fibrosis was established by intraperitoneal injection of CCl₄. Mice were randomly assigned to a Control group, a CCl₄ group, Geniposide group, and a Pirfenidone group (positive control group). Liver function indicators and antioxidant indicators were measured, while histopathological changes and collagen deposition were evaluated by hematoxylin and eosin and Sirius Red staining. Expression of PERK-CHOP pathway-related and apoptosis-related molecules was assessed by western blotting and reverse transcription-quantitative PCR. HSC activation and hepatocyte apoptosis were determined by immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. The results demonstrated that geniposide significantly improved liver function, reduced oxidative stress, alleviated histopathological injury, and decreased collagen deposition and hydroxyproline content in CCl₄-treated mice. Furthermore, geniposide significantly decreased the ratios of phosphorylated (p-) PERK/PERK and p-eukaryotic initiation factor 2α (eIF2α)/eIF2α protein expression and reduced CHOP protein levels, while downregulating the pro-apoptotic proteins Bcl-2-associated X protein and cysteine-aspartic protease 3 and upregulating the anti-apoptotic protein B-cell lymphoma 2. In addition, the number of TUNEL-positive hepatocytes exhibited a declining trend. In conclusion, geniposide alleviates CCl₄-induced liver fibrosis, with its protective effects being associated with suppression of the PERK-CHOP signaling pathway and hepatocyte apoptosis.