2. Academic Validation
  3. Proanthocyanidin and mitoglitazone suppress lipogenesis by targeting ferroptosis in metabolic dysfunction-associated steatohepatitis

Proanthocyanidin and mitoglitazone suppress lipogenesis by targeting ferroptosis in metabolic dysfunction-associated steatohepatitis

  • Naunyn Schmiedebergs Arch Pharmacol. 2025 May 19. doi: 10.1007/s00210-025-04271-z.
Sohair M Abd El-Naby 1,  Naglaa F Khedr 2,  Nahla E El-Ashmawy 1 3,  Amera O Ibrahim 4
Affiliations

Affiliations

  • 1 Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt.
  • 2 Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt. naglaa.khedr@pharm.tanta.edu.eg.
  • 3 Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt, El Sherouk, Postal Code: 11837, Egypt.
  • 4 Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt. amera.ibrahim@pharm.tanta.edu.eg.
PMID: 40387928 DOI: 10.1007/s00210-025-04271-z
Abstract

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.

Keywords

Ferroptosis; Glutathione peroxidase X4; Metabolic dysfunction-associated steatohepatitis; Mitoglitazone; Proanthocyanidin.

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