El-Naby Sohair M Abd, Khedr Naglaa F, El-Ashmawy Nahla E, Ibrahim Amera O
Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt.
Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt, El Sherouk, Postal Code: 11837, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 19. doi: 10.1007/s00210-025-04271-z.
Metabolic dysfunction-associated steatohepatitis (MASH) can progress to liver cirrhosis, increasing mortality risk. The study investigates the role of ferroptosis-an inflammatory cell death mechanism-in MASH and evaluates the therapeutic effects of mitoglitazone and proanthocyanidin in targeting ferroptosis to mitigate MASH progression. Forty male albino mice were divided into five groups (n = 8): normal control (NC) fed a standard chow diet and given 2% DMSO; MASH group was maintained on MASH protocol (high fructose-high fat diet); mitoglitazone (Mito) group was kept on MASH protocol and given Mito (10 mg/kg/day); proanthocyanidin (Pro) group was kept on MASH protocol and given Pro (150 mg/kg/day); Mito + Pro co-treated group was given Mito and Pro parallel with MASH protocol, all treatments for 12 weeks. MASH induction significantly (p < 0.001) increased liver weight, liver index, serum liver enzymes (ALT & AST), serum glucose, insulin, insulin resistance (HOMA-IR), lipid profile (total cholesterol, triglycerides, LDL-C), ferroptosis biomarkers (total iron, soluble transferrin receptor-1 (sTfR1), and expression of liver acyl-CoA synthetase long-chain family member 4 (ACSL4) with diffused macrovesicular severe steatosis, and inflammatory cells infiltration in liver tissues compared to NC. However, HDL-cholesterol, ferroptosis biomarkers (liver glutathione peroxidase X4 (GPX4), and total glutathione peroxidase (GPX) activities and glutathione (GSH) content) were reduced significantly (p < 0.001) in MASH group compared to NC. On the other hand, Mito, Pro, and their combination significantly improved ferroptotic biomarkers (GSH, GPX4, sTFR1, and total iron and ACSL-4 gene expression), glucose homeostasis, lipid profile, liver enzymes, and histology compared to MASH group. Combining the insulin-sensitizing properties with targeting of ferroptosis, by the co-treatment with mitoglitazone (MSDC-0160) and proanthocyanidin, could be beneficial in inhibition of lipogenesis with retardation of MASH development in mice.
代谢功能障碍相关脂肪性肝炎（MASH）可进展为肝硬化，增加死亡风险。本研究调查了铁死亡（一种炎症性细胞死亡机制）在MASH中的作用，并评估了米格列酮和原花青素针对铁死亡减轻MASH进展的治疗效果。将40只雄性白化小鼠分为五组（n = 8）：正常对照组（NC），喂食标准饲料并给予2%二甲基亚砜；MASH组，采用MASH方案（高果糖-高脂肪饮食）；米格列酮（Mito）组，采用MASH方案并给予米格列酮（10毫克/千克/天）；原花青素（Pro）组，采用MASH方案并给予原花青素（150毫克/千克/天）；Mito + Pro联合治疗组，在采用MASH方案的同时给予米格列酮和原花青素，所有治疗均持续12周。与NC组相比，MASH诱导显著（p < 0.001）增加了肝脏重量、肝脏指数、血清肝酶（ALT和AST）、血清葡萄糖、胰岛素、胰岛素抵抗（HOMA-IR）、血脂谱（总胆固醇、甘油三酯、低密度脂蛋白胆固醇）、铁死亡生物标志物（总铁、可溶性转铁蛋白受体-1（sTfR1）以及肝脏酰基辅酶A合成酶长链家族成员4（ACSL4）的表达），并伴有弥漫性大泡性严重脂肪变性以及肝组织中的炎症细胞浸润。然而，与NC组相比，MASH组的高密度脂蛋白胆固醇、铁死亡生物标志物（肝脏谷胱甘肽过氧化物酶X4（GPX4）、总谷胱甘肽过氧化物酶（GPX）活性以及谷胱甘肽（GSH）含量）显著降低（p < 0.001）。另一方面，与MASH组相比，米格列酮、原花青素及其组合显著改善了铁死亡生物标志物（GSH、GPX4、sTFR1、总铁以及ACSL-4基因表达）、葡萄糖稳态、血脂谱、肝酶以及组织学。米格列酮（MSDC-0160）和原花青素联合治疗，将胰岛素增敏特性与铁死亡靶向相结合，可能有助于抑制脂肪生成并延缓小鼠MASH的发展。
