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

Sohair M Abd El-Naby1, Naglaa F Khedr2, Nahla E El-Ashmawy1,3

  • 1Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt.

Naunyn-Schmiedeberg'S Archives of Pharmacology
|May 19, 2025
PubMed

Insights

Metabolic dysfunction-associated steatohepatitis (MASH) can lead to cirrhosis. Mitoglitazone and proanthocyanidin treatments targeting ferroptosis show promise in mitigating MASH progression and improving liver health in mice.

Area of Science:

  • Hepatology
  • Cellular Biology
  • Pharmacology

Background:

  • Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with increased mortality risk.
  • Ferroptosis, a regulated form of inflammatory cell death, plays a significant role in MASH pathogenesis.
  • Current therapeutic strategies for MASH are limited, necessitating novel treatment approaches targeting underlying mechanisms.

Purpose of the Study:

  • To investigate the role of ferroptosis in MASH development.
  • To evaluate the therapeutic efficacy of mitoglitazone and proanthocyanidin in targeting ferroptosis to ameliorate MASH.
  • To assess the combined effects of mitoglitazone and proanthocyanidin on MASH progression.

Main Methods:

  • Forty male albino mice were divided into five groups: normal control, MASH induction, MASH with mitoglitazone, MASH with proanthocyanidin, and MASH with combined treatment.
  • MASH was induced using a high-fructose-high-fat diet for 12 weeks.
  • Therapeutic interventions (mitoglitazone and proanthocyanidin) were administered daily for 12 weeks, with biochemical, histological, and molecular analyses performed.

Main Results:

  • MASH induction significantly increased liver enzymes, glucose, insulin resistance, dyslipidemia, and ferroptosis biomarkers (iron, sTfR1, ACSL4), alongside severe steatosis and inflammation.
  • Mitoglitazone and proanthocyanidin, individually and in combination, significantly improved ferroptosis markers (GSH, GPX4), glucose homeostasis, lipid profile, liver enzymes, and liver histology compared to the MASH group.
  • Combined treatment demonstrated enhanced benefits in mitigating MASH-associated pathology.

Conclusions:

  • Ferroptosis is a key mechanism in MASH progression.
  • Mitoglitazone and proanthocyanidin exhibit therapeutic potential by targeting ferroptosis and improving metabolic parameters in MASH.
  • Combination therapy holds promise for inhibiting lipogenesis and retarding MASH development.
Keywords:
FerroptosisGlutathione peroxidase X4Metabolic dysfunction-associated steatohepatitisMitoglitazoneProanthocyanidin

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