Wang Linya, Yu Hongzhuan, Wang Dongxian, Yin Guoliang, Chen Suwen, Zhang Xin, Yu Wenfei, Meng Decheng, Liu Hongshuai, Jiang Wenying, Zhang Fengxia
Shandong University of Traditional Chinese Medicine, Jinan, China.
Weifang Traditional Chinese Medicine Hospital, Shandong, China.
J Nutr Biochem. 2025 Jun;140:109886. doi: 10.1016/j.jnutbio.2025.109886. Epub 2025 Feb 27.
The most prevalent liver condition globally is non-alcoholic fatty liver disease (NAFLD), for which no approved therapies currently exist. Diosgenin, an important component in plants from the Leguminosae, Dioscoreaceae, and Solanaceae families, has demonstrated considerable anti-inflammatory and antioxidant effects. Nonetheless, the specific mechanism by which it may act in managing NAFLD remains unclear. Our research aims to explore the effects and molecular mechanisms of DG on NAFLD by utilizing both in vivo and in vitro experimental approaches. To investigate the effect of DG on hepatic steatosis, we used Sprague-Dawley rats induced by a high-fat diet (HFD) and HepG2 cells exposed to free fatty acids. Oil red O staining and hematoxylin-eosin (H&E) staining were used to explore lipid accumulation and hepatic degeneration. ROS staining, SOD, MDA, and Fekits were used to detect the indexes related to oxidative stress in ferroptosis in hepatic tissues and cells. IFSP1 and pcDNA3.1-ACSL4 plasmid were used to knock down Ferroptosis suppressor protein1 (FSP1) and promote the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) in HepG2 cells. DG improved lipid metabolism disorders and liver damage induced by a high-fat diet in rats with NAFLD. Furthermore, the administration of DG notably decreased oxidative stress levels and liver Fe concentrations in rats. Additionally, in vitro experiments demonstrated that DG treatment markedly attenuated ferroptosis and ROS accumulation in HepG2 cells induced by FFAs. Moreover, overexpression of hepatic ACSL4 expression by pcDNA3.1-ACSL4 plasmid promoted the regulatory effects of DG on LPCAT3 and ALOX15. Our research shows that DG can alleviate NAFLD by regulating the FSP1/COQ10 pathway of the ferroptosis defense system and the ACSL4/LPCAT3/ALOX15 pathway of the ferroptosis execution system. Therefore, DG may serve as a novel inhibitor of ferroptosis for the treatment of NAFLD.
全球最普遍的肝脏疾病是非酒精性脂肪性肝病（NAFLD），目前尚无获批的治疗方法。薯蓣皂苷元是豆科、薯蓣科和茄科植物中的一种重要成分，已显示出相当大的抗炎和抗氧化作用。然而，其在管理NAFLD中可能发挥作用的具体机制仍不清楚。我们的研究旨在通过体内和体外实验方法探索薯蓣皂苷元（DG）对NAFLD的影响及其分子机制。为了研究DG对肝脂肪变性的影响，我们使用了高脂饮食（HFD）诱导的Sprague-Dawley大鼠和暴露于游离脂肪酸的HepG2细胞。采用油红O染色和苏木精-伊红（H&E）染色来探究脂质蓄积和肝脏变性情况。采用活性氧（ROS）染色、超氧化物歧化酶（SOD）、丙二醛（MDA）和铁死亡检测试剂盒来检测肝组织和细胞中铁死亡相关的氧化应激指标。使用干扰铁死亡抑制蛋白1（FSP1）的小干扰RNA（siFSP1）和pcDNA3.1-酰基辅酶A合成酶长链家族成员4（ACSL4）质粒来敲低HepG2细胞中的FSP1并促进ACSL4的表达。DG改善了NAFLD大鼠高脂饮食诱导的脂质代谢紊乱和肝损伤。此外，给予DG显著降低了大鼠的氧化应激水平和肝脏铁浓度。此外，体外实验表明，DG处理显著减轻了游离脂肪酸（FFAs）诱导的HepG2细胞中的铁死亡和ROS蓄积。此外，pcDNA3.1-ACSL4质粒过表达肝脏ACSL4可促进DG对溶血磷脂酰胆碱酰基转移酶3（LPCAT3）和花生四烯酸脂氧合酶15（ALOX15）的调节作用。我们的研究表明，DG可通过调节铁死亡防御系统的FSP1/辅酶Q10途径和铁死亡执行系统的ACSL4/LPCAT3/ALOX15途径来减轻NAFLD。因此，DG可能作为一种新型的铁死亡抑制剂用于治疗NAFLD。
