UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 μM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC₅₀ value of 159 μM. In CCl₄-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg⁻¹ · d⁻¹, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl₄-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.

UDP-葡萄糖神经酰胺葡萄糖基转移酶 (UGCG) 是鞘糖脂 (GSL) 代谢中第一个产生葡萄糖神经酰胺 (GlcCer) 的关键酶。 UGCG 合成增加与人类癌症的细胞增殖、侵袭和多药耐药性相关。在这项研究中，我们研究了 UGCG 在肝纤维化发病机制中的作用。我们首先发现 UGCG 在纤维化肝脏和活化的肝星状细胞 (HSC) 中过度表达。在人 HSC-LX2 细胞中，用 PDMP 抑制 UGCG 或敲除 UGCG 会抑制 HSC 活化生物标志物（α-SMA 和胶原蛋白 I）的表达。此外，PDMP (40 μM) 预处理会损害溶酶体稳态并阻断自噬过程，导致视黄酸信号通路激活和脂滴积累。在探索了UGCG的结构和激活HSC的关键催化残基后，我们进行了虚拟筛选、分子相互作用和分子对接实验，证明了中药丹参中的丹酚酸B（SAB）作为具有IC的UGCG抑制剂₅₀值为 159 μM。在CCl ₄诱导的小鼠肝纤维化中，腹腔注射SAB（30 mg·kg ^-1 ·d ^-1 ，持续4周）通过抑制HSC的活化和胶原沉积，显着减轻肝纤维化。此外，SAB在CCl ₄诱导的肝纤维化中表现出更好的抗炎作用。这些结果表明 UGCG 可能代表肝纤维化的治疗靶点； SAB可以作为UGCG的抑制剂，有望成为治疗肝纤维化的候选药物。