School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China.
Int J Mol Sci. 2023 May 15;24(10):8795. doi: 10.3390/ijms24108795.
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with a global prevalence of 25%. However, the medicines approved by the FDA or EMA are still not commercially available for the treatment of NAFLD. The NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome plays a crucial role in inflammatory responses, and the mechanisms related to steatohepatitis have been sufficiently clarified. NLRP3 has been widely evaluated as a potential target for multiple active agents in treating NAFLD. As a quercetin glycoside, isoquercitrin (IQ) has a broad inhibitory effect on oxidative stress, cancers, cardiovascular diseases, diabetes, and allergic reactions in vitro and in vivo. This study aimed to investigate the undercover mechanism of IQ in the treatment of NAFLD, particularly in anti-steatohepatitis, by suppressing the NLRP3 inflammasome. In this study, a methionine-choline-deficient induced steatohepatitis mice model was used to explore the effect of IQ on NAFLD treatment. Further mechanism exploration based on transcriptomics and molecular biology revealed that IQ inhibited the activated NLRP3 inflammasome by down-regulating the expression of heat shock protein 90 (HSP90) and suppressor of G-two allele of Skp1 (SGT1). In conclusion, IQ could alleviate NAFLD by inhibiting the activated NLRP3 inflammasome by suppressing the expression of HSP90.
非酒精性脂肪性肝病（NAFLD）是一种全球性疾病，其患病率为 25%。然而，目前还没有获得 FDA 或 EMA 批准的药物可用于治疗 NAFLD。核苷酸结合寡聚化结构域样受体热蛋白结构域相关蛋白 3（NLRP3）炎性小体在炎症反应中起着至关重要的作用，且与脂肪性肝炎相关的机制已得到充分阐明。NLRP3 已被广泛评估为治疗 NAFLD 的多种活性药物的潜在靶点。作为一种槲皮素糖苷，异槲皮苷（IQ）在体外和体内对氧化应激、癌症、心血管疾病、糖尿病和过敏反应具有广泛的抑制作用。本研究旨在探讨 IQ 通过抑制 NLRP3 炎性小体治疗 NAFLD，特别是抗脂肪性肝炎的潜在作用机制。本研究采用蛋氨酸-胆碱缺乏诱导的脂肪性肝炎小鼠模型，探讨 IQ 对 NAFLD 治疗的影响。基于转录组学和分子生物学的进一步机制探索表明，IQ 通过下调热休克蛋白 90（HSP90）和 Skp1 的 G 二聚体抑制因子（SGT1）的表达来抑制激活的 NLRP3 炎性小体。综上所述，IQ 通过抑制 HSP90 的表达来抑制激活的 NLRP3 炎性小体，从而减轻 NAFLD。
