Ginkgolide A alleviated liver fibrosis by modulating PI3K/AKT/NF-κB signaling to inhibit M1 macrophage polarization and macrophage-HSC crosstalk.
TL;DR
GA alleviated LF by modulating PI3K/AKT/NF-κB signaling to inhibit M1 macrophage polarization and the pathogenic macrophage-HSC interaction, highlighting its potential as an immunomodulatory therapeutic candidate for LF.
Abstract
Liver fibrosis (LF) is a progressive pathological process driven by chronic hepatocyte injury and aberrant wound healing, culminating in excessive extracellular matrix (ECM) deposition primarily mediated by activated hepatic stellate cells (HSCs). A dysregulated hepatic immune microenvironment, orchestrated in large part by macrophages, plays a critical role in driving HSCs activation. Ginkgolide A (GA), a bioactive diterpenoid lactone from Ginkgo biloba leaves, possesses potent anti-inflammatory and antioxidant activities. However, its role and underlying mechanism in LF, particularly via modulation of macrophage-HSC crosstalk, remain unclear. In this study, we demonstrate that GA inhibited LPS-induced M1 macrophage polarization and TGF-β1-induced HSCs activation. In vivo, GA exerted potent antifibrotic effects in both NASH-associated and CCl4-induced liver fibrosis. Network pharmacology analysis identified the PI3K/AKT/NF-κB signaling pathway as a key pathway targeted by GA in LF, and molecular docking and dynamics simulations further supported the interaction between GA and PI3K. Mechanistically, GA inhibited PI3K/AKT/NF-κB signaling, and rescue experiments using a PI3K activator confirmed that this pathway is functionally required for GA-mediated suppression of M1 macrophage polarization. Collectively, GA alleviated LF by modulating PI3K/AKT/NF-κB signaling to inhibit M1 macrophage polarization and the pathogenic macrophage-HSC interaction, highlighting its potential as an immunomodulatory therapeutic candidate for LF.