Salvianic acid A alleviates hepatic fibrosis by inhibiting the AKT1/NF-κB axis.

Abstract

Hepatic fibrosis (HF) is a crucial and reversible stage, yet there is a paucity of effective clinical antifibrotic drugs. Salvianic acid A (SAA) has shown antifibrotic potential in preliminary studies; however, its molecular mechanisms and potential targets remain incompletely understood. To evaluate the therapeutic efficacy and mechanisms of SAA in mitigating HF, we employed a carbon tetrachloride (CCl4)-induced HF mouse model. In parallel, we used transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells and primary mouse hepatic stellate cells (HSCs) for in vitro studies. In CCl4-induced mice, SAA markedly improved liver function and suppressed HF, as evidenced by significant reduction in α-smooth muscle actin and collagen I expression and alleviation of inflammatory response. Similar antifibrotic and anti-inflammatory effects were observed in vitro. To investigate the targets and mechanism of SAA in HF, we employed network pharmacology, molecular docking, molecular dynamics simulations, and microscale thermophoresis. We found that SAA was predicted to interact with the allosteric pocket of RAC-alpha serine/threonine-protein kinase 1 (AKT1), accompanied by inhibition of AKT1 phosphorylation and the downstream nuclear factor-kappa B (NF-κB) signaling. To further explore the involvement of AKT1 in SAA's antifibrotic effects, we used the AKT activator SC79. In CCl4-induced mice, SC79 partly reversed the antifibrotic effects of SAA. Consistently, we observed that SC79 partially restored the inflammatory and fibrotic markers in TGF-β1-simulated HSCs, counteracting the inhibitory efficacy of SAA. Our findings suggest that SAA exerts antifibrotic effects in part through suppression of the AKT1/NF-κB axis and may represent a promising therapeutic candidate for HF.