Chelerythrine-mediated targeting of NF-κB and Nrf2 pathways alleviates liver injury in a carbon tetrachloride-induced liver fibrosis mouse model.

Abstract

Background and aims: This study aimed to investigate the mechanism and efficacy of chelerythrine (CHE) in treating carbon tetrachloride (CCl₄)-induced liver fibrosis, with a particular focus on the nuclear factor-erythroid-related factor-2 (Nrf2) and nuclear factor-kappa-B (NF-κB) signaling pathways.

Methods: Mice were induced with CCl₄ for eight weeks and categorized into the control group, CCl₄ model group, and CHE low (7 mg/kg/d, ig,), medium (14 mg/kg/d, ig), and high-dose (28 mg/kg/d, ig) groups with 10 animals in each group. Following CHE treatment, liver sample morphology was assessed using multiple immunohistochemistry, and serum biochemical indicators were measured. ELISA was used to determine IL-10, IL-1β, and TNF-α contents. Western blotting and RT-PCR were employed to analyze protein and mRNA levels of α-SMA, Col-I, fibronectin, Nrf2, HO-1, NQO1, GCLc, GCLm, NF-κB, p-NF-κB, IκBα, and p-IκBα. Nrf2 knockout mice were used to assess the impact of CHE on the Nrf2 signaling pathway.

Results: The findings demonstrated that CHE significantly ameliorated oxidative damage, inflammatory response, and liver fibrosis in CCl₄-induced mice. CHE treatment increased Nrf2 expression and its target proteins, including HO-1 and GCLc, an effect not observed in Nrf2 knockout mice. In addition, CHE reduced NF-κB expression levels.

Conclusions: These results suggest that CHE can alleviate liver fibrosis in CCl₄-induced mice by modulating NF-κB/IκBα and Nrf2 signaling pathways. These findings propose CHE as a potential novel anti-liver fibrosis drug.