Liu Rong, Zhang Yi, Liu Min, Shang Zhiyin, Song Shu, Zhang Yajun, Zhou Yingqun, Tu Chuantao
Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Liver disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
J Nutr Biochem. 2025 Feb;136:109808. doi: 10.1016/j.jnutbio.2024.109808. Epub 2024 Nov 19.
Isoliquiritigenin (ISL), a flavonoid derived from licorice root, has diverse biological and pharmacological properties. This study aimed to investigate the hepatoprotective effects and mechanism of action of ISL on the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH). C57BL/6 mice fed a chow diet or choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) received ISL (10 mg/kg) or vehicle daily via oral administration. To further explore the mechanism of ISL in MASH pathogenesis, AML12 cells were exposed to palmitic acid (PA) as an in vitro model of lipid toxicity. The results showed that, compared with vehicle-treated mice, ISL treatment alleviated liver injury, steatosis, inflammation, and fibrosis in MASH mice. Moreover, ISL treatment reduced the recruitment of CD68 macrophages and activated hepatic stellate cells (HSCs) in MASH livers. In vitro experiments showed that ISL reduced lipid accumulation and mitigated inflammatory responses in PA-induced AML12 cells. Notably, RNA-sequencing analyses revealed that the anti-MASH effect of ISL enhanced autophagy via the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. This was further validated by assessing autophagy markers in both MASH liver tissues and PA-stimulated AML12 cells in vitro. Additionally, molecular docking analysis demonstrated that the target proteins of ISL exhibited strong binding affinity to PIK3 isoforms. In conclusion, our findings highlight that ISL mitigates MASH and fibrosis in mice by promoting autophagy through the PI3K/Akt/mTOR signaling pathway, providing reliable evidence to support further studies on MASH in humans.
异甘草素（ISL）是一种从甘草根中提取的黄酮类化合物，具有多种生物学和药理学特性。本研究旨在探讨ISL对代谢功能障碍相关脂肪性肝炎（MASH）发病机制的肝保护作用及其作用机制。将喂食普通饲料或胆碱缺乏、L-氨基酸限定的高脂饮食（CDAHFD）的C57BL/6小鼠每日经口给予ISL（10 mg/kg）或赋形剂。为了进一步探究ISL在MASH发病机制中的作用机制，将AML12细胞暴露于棕榈酸（PA）中，作为脂质毒性的体外模型。结果表明，与赋形剂处理的小鼠相比，ISL治疗减轻了MASH小鼠的肝损伤、脂肪变性、炎症和纤维化。此外，ISL治疗减少了MASH肝脏中CD68巨噬细胞的募集并激活了肝星状细胞（HSC）。体外实验表明，ISL减少了PA诱导的AML12细胞中的脂质积累并减轻了炎症反应。值得注意的是，RNA测序分析显示，ISL的抗MASH作用通过磷酸肌醇3激酶（PI3K）/蛋白激酶B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路增强了自噬。通过评估MASH肝组织和体外PA刺激的AML12细胞中的自噬标志物，进一步验证了这一点。此外，分子对接分析表明，ISL的靶蛋白对PIK3亚型表现出强烈的结合亲和力。总之，我们的研究结果表明，ISL通过PI3K/Akt/mTOR信号通路促进自噬，减轻小鼠的MASH和纤维化，为支持进一步在人类中开展MASH研究提供了可靠的证据。
