Shi Wei, Xu Guang, Gao Yuan, Zhao Jun, Liu Tingting, Zhao Jia, Yang Huijie, Wei Ziying, Li Hui, Xu An-Long, Bai Zhaofang, Xiao Xiaohe
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.
J Transl Med. 2023 Oct 7;21(1):700. doi: 10.1186/s12967-023-04380-4.
Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury, inflammation, and fibrosis in various stages. More than 20% of patients with NASH will progress to cirrhosis. Currently, there is a lack of clinically effective drugs for treating NASH, as improving liver histology in NASH is difficult to achieve and maintain through weight loss alone. Hence, the present study aimed to investigate potential therapeutic drugs for NASH.
BMDMs and THP1 cells were used to construct an inflammasome activation model, and then we evaluated the effect of epalrestat on the NLRP3 inflammasome activation. Western blot, real-time qPCR, flow cytometry, and ELISA were used to evaluate the mechanism of epalrestat on NLRP3 inflammasome activation. Next, MCD-induced NASH models were used to evaluate the therapeutic effects of epalrestat in vivo. In addition, to evaluate the safety of epalrestat in vivo, mice were gavaged with epalrestat daily for 14 days.
Epalrestat, a clinically effective and safe drug, inhibits NLRP3 inflammasome activation by acting upstream of caspase-1 and inducing ASC oligomerization. Importantly, epalrestat exerts its inhibitory effect on NLRP3 inflammasome activation by inhibiting the activation of aldose reductase. Further investigation revealed that the administration of epalrestat inhibited NLRP3 inflammasome activation in vivo, alleviating liver inflammation and improving NASH pathology.
Our study indicated that epalrestat, an aldose reductase inhibitor, effectively suppressed NLRP3 inflammasome activation in vivo and in vitro and might be a new therapeutic approach for NASH.
非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病（NAFLD）的一种进行性炎症亚型，其特征是肝细胞损伤、炎症和不同阶段的纤维化。超过20%的NASH患者会进展为肝硬化。目前，缺乏治疗NASH的临床有效药物，因为仅通过减肥难以实现并维持NASH患者肝脏组织学的改善。因此，本研究旨在探究NASH的潜在治疗药物。
使用骨髓来源的巨噬细胞（BMDMs）和人单核细胞白血病细胞系（THP1）构建炎性小体激活模型，然后评估依帕司他对NLRP3炎性小体激活的影响。采用蛋白质免疫印迹法（Western blot）、实时定量聚合酶链反应（real-time qPCR）、流式细胞术和酶联免疫吸附测定（ELISA）评估依帕司他对NLRP3炎性小体激活的作用机制。接下来，使用蛋氨酸胆碱缺乏（MCD）诱导的NASH模型评估依帕司他在体内的治疗效果。此外，为了评估依帕司他在体内的安全性，小鼠每天灌胃依帕司他，持续14天。
依帕司他是一种临床有效且安全的药物，通过作用于半胱天冬酶-1上游并诱导凋亡相关斑点样蛋白（ASC）寡聚化来抑制NLRP3炎性小体激活。重要的是，依帕司他通过抑制醛糖还原酶的激活对NLRP3炎性小体激活发挥抑制作用。进一步研究表明，给予依帕司他可抑制体内NLRP3炎性小体激活，减轻肝脏炎症并改善NASH病理状态。
我们的研究表明，醛糖还原酶抑制剂依帕司他在体内和体外均能有效抑制NLRP3炎性小体激活，可能是一种治疗NASH的新方法。
