Guizhi Fuling Wan attenuates tetrachloromethane-induced hepatic fibrosis in rats via PTEN/AKT/mTOR signaling pathway

Abstract

Ethnopharmacological relevanceTreatment options for hepatic fibrosis, a prevalent liver condition closely linked to cirrhosis, are currently limited. While Guizhi Fuling Wan (GFW), a pill derived from traditional Chinese herbs, has been reported to possess hepatoprotective properties, its therapeutic effect and mechanism in hepatic fibrosis remain elusive. Aim of the studyThis study aimed to evaluate the anti-fibrotic impact of GFW and its underlying mechanisms in both in vivo and in vitro settings. Materials and methodsTetrachloromethane (CCl4) was used to induce hepatic fibrosis in male rats. In vitro, activation of hepatic stellate cells (HSCs) was triggered by platelet-derived growth factor-BB (PDGF-BB). In vivo, liver function, pathological alterations, and HSC activation were evaluated. Additionally, the impact of GFW on the activated phenotypes of Lieming Xu-2 (LX-2) cells was examined in vitro. Network pharmacology was employed to identify the potential targets of GFW in hepatic fibrosis. Lastly, the impact of GFW on the PTEN/AKT/mTOR pathway and PTEN ubiquitination in HSCs was investigated. ResultsGFW alleviated CCl4-induced liver damage and scarring in rats in a dose-dependent manner and suppressed HSC activation in vivo. Moreover, GFW inhibited the proliferation, migration, differentiation, and extracellular matrix (ECM) production of activated HSCs in vitro. GFW also promoted autophagy and apoptosis of HSCs. Meanwhile, network pharmacology and in vitro studies suggested that GFW inhibits the AKT/mTOR pathway by preventing PTEN degradation by suppressing ubiquitination. ConclusionGFW attenuates Ccl4-induced hepatic fibrosis in male rats by regulating the PTEN/AKT/mTOR signaling pathway, positioning it as a potential candidate for the treatment of hepatic fibrosis.