Saikosaponin-d alleviates hepatic stellate cell activation and liver fibrosis by inhibiting the TGF-β1/Smads signaling pathway and blocking the EMT process

Figure 4 The mechanism diagram of saikosaponin-d suppressing epithelial-mesenchymal transition progression and alleviating liver fibrosis by inhibiting the transforming growth factor-β1/Smad signaling pathway. Upon hepatic injury or stimulation by endotoxins and inflammatory cytokines, hepatic stellate cells (HSCs), Kupffer cells, hepatocytes, and liver sinusoidal endothelial cells secrete substantial amounts of transforming growth factor-β1 (TGF-β), contributing to hepatic immune regulation and inflammation. HSCs are key cellular players in the fibrogenic process. In response to liver injury, quiescent HSCs undergo activation and transition into activated HSCs, which secrete excessive extracellular matrix, driving fibrosis progression. Activated HSCs also secrete TGF-β, a major mediator of liver fibrosis. TGF-β signals through a heteromeric complex of two serine/threonine kinase receptors, type I and type II, which phosphorylate Smad2/Smad3 proteins. This leads to the activation of fibrogenic mediators, including collagen, α-smooth muscle actin, and fibronectin. Additionally, TGF-β1 is a potent inducer of the epithelial-mesenchymal transition, a process where epithelial cells lose their characteristic phenotype and acquire mesenchymal features, contributing to fibrosis. Saikosaponin-d attenuates HSC activation and mitigates liver fibrosis progression, partly by inhibiting the TGF-β1/Smad signaling pathway and the downstream epithelial-mesenchymal transition progression. ROS: Reactive oxygen species; TGF-β1: Transforming growth factor-beta 1; SSd: Saikosaponin-d; LSEC: Liver sinusoidal endothelial cell; TGF-βR: Transforming growth factor-beta receptor; EMT: Epithelial-mesenchymal transition; TNF-α: Tumor necrosis factor-alpha; IL-1β: Interleukin-1 beta; HSC: Hepatic stellate cell.