Hepatic stellate cells (HSCs) are essential drivers of fibrogenesis. Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis. 18beta-glycyrrhetinic acid (18β-GA) is a natural compound that exists widely in herbal medicines, such as Glycyrrhiza uralensis Fisch, which is used for treating multiple liver diseases, especially in Asia. In the present study, we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs. 18β-GA inhibited the expression of α-smooth muscle actin and collagen type I alpha-1. Using a chemoproteomic approach derived from activity-based protein profiling, together with cellular thermal shift assay and surface plasmon resonance, we found that 18β-GA covalently targeted peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2) proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities. 18β-GA induced the elevation of reactive oxygen species (ROS), resulting in the apoptosis of activated HSCs. PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs. Collectively, our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis, highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis.

肝星状细胞 (HSC) 是纤维发生的重要驱动因素。诱导活化的 HSC 凋亡是治疗肝纤维化的一种有前途的策略。18β-甘草次酸 (18β-GA) 是一种天然化合物，广泛存在于草药中，如甘草Fisch，用于治疗多种肝病，尤其是在亚洲。在本研究中，我们证明 18β-GA 通过诱导活化的 HSC 细胞凋亡来减少肝纤维化。18β-GA 抑制 α-平滑肌肌动蛋白和 I 型胶原蛋白 α-1 的表达。使用源自基于活性的蛋白质谱分析的化学蛋白质组学方法，连同细胞热位移测定和表面等离子体共振，我们发现 18β-GA 通过与活性半胱氨酸残基和从而抑制了它们的酶活性。18β-GA 诱导活性氧 (ROS) 升高，导致活化的 HSC 凋亡。PRDX1敲低还导致活化的 HSC 中 ROS 介导的细胞凋亡。总的来说，我们的研究结果揭示了 18β-GA 在改善肝纤维化方面的靶蛋白和分子机制，突出了 18β-GA 作为一种新型肝纤维化治疗药物的未来发展。