Yan Yiming, Yang Ningxi, Qin Fanglin, Hao Yarong
Department of Geriatric, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan 430060, China.
Biomedicines. 2024 Nov 28;12(12):2728. doi: 10.3390/biomedicines12122728.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic lipid accumulation, and echinacoside (ECH) has demonstrated antioxidant and anti-inflammatory effects across multiple conditions, it has demonstrated hepatoprotective effects. Ferroptosis represents a novel mechanism of cell demise, differing from apoptosis and autophagy. Emerging research indicates that ferroptosis in hepatocytes plays a role in the development of alcoholic liver disease. This study aimed to reveal the effect and potential mechanism of ECH on MASLD. The effect of ECH on the viability, lipid deposition, lipid peroxidation, mitochondrial of OA/PA-treated HepG2 cells were evaluated by Cell Counting Kit-8 assay, JC-1 and immunofluorescence assay. Meanwhile, the mechanism of ECH was assessed using transmission electron microscopy and immunofluorescence analysis. Moreover, db/db mice, a spontaneous type 2 diabetes mode, were intragastrically administered ECH by 300 mg/kg or an equivalent volume of saline. Body weight, lipids, and liver function were measured. liver pathology was performed. The mechanism of ECH in vivo was analyzed using Western blot and immunofluorescence analysis in db/db mice. ECH attenuated lipid deposition, lipid peroxidation and ferroptosis induced by OA/PA in HepG2 cells. Mitochondrial morphology and function in HepG2 cells were also preserved by ECH. In db/db mice model of MASLD, ECH markedly ameliorated liver hepatocellular ballooning, inflammatory cell infiltration in the portal area, and fibrous tissue proliferation. ECH also increased the expression of Nrf2, HMOX-1, SLC7A11, and GPX4, and decreased the expression of ACSL4 in liver tissues. Mechanically, ECH repressed ferroptosis by activating the Nrf2/HO-1 signaling pathway. Our research revealed that ECH has the capability to modulate ferroptosis via the Nrf2-HMOX1pathway, consequently mitigating the progression of MASLD. This suggests that ECH has a potential role in the treatment of MASLD.
代谢功能障碍相关脂肪性肝病（MASLD）是一种以肝脏脂质蓄积为特征的慢性肝病，而紫锥菊苷（ECH）在多种情况下均表现出抗氧化和抗炎作用，已证明其具有肝脏保护作用。铁死亡代表一种不同于凋亡和自噬的新型细胞死亡机制。新出现的研究表明，肝细胞中的铁死亡在酒精性肝病的发展中起作用。本研究旨在揭示ECH对MASLD的作用及潜在机制。通过细胞计数试剂盒-8法、JC-1和免疫荧光法评估ECH对油酸/棕榈酸（OA/PA）处理的HepG2细胞活力、脂质沉积、脂质过氧化、线粒体的影响。同时，使用透射电子显微镜和免疫荧光分析评估ECH的作用机制。此外，将自发2型糖尿病模型db/db小鼠以300mg/kg的剂量或等体积的生理盐水进行胃内给药ECH。测量体重、血脂和肝功能。进行肝脏病理学检查。使用蛋白质免疫印迹法和免疫荧光分析对db/db小鼠体内ECH的作用机制进行分析。ECH减轻了OA/PA诱导的HepG2细胞中的脂质沉积、脂质过氧化和铁死亡。ECH还保留了HepG2细胞中的线粒体形态和功能。在MASLD的db/db小鼠模型中，ECH显著改善了肝细胞气球样变、门管区炎性细胞浸润和纤维组织增生。ECH还增加了肝脏组织中核因子E2相关因子2（Nrf2）、血红素加氧酶-1（HMOX-1）、溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的表达，并降低了长链脂酰辅酶A合成酶4（ACSL4）的表达。机制上，ECH通过激活Nrf2/HO-1信号通路抑制铁死亡。我们的研究表明，ECH有能力通过Nrf2-HMOX1途径调节铁死亡，从而减轻MASLD的进展。这表明ECH在MASLD的治疗中具有潜在作用。
