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

TL;DR

This study shows that targeting ferroptosis with mitoglitazone and proanthocyanidin can reduce liver damage and lipogenesis in mice with MASH.

Contribution

The study introduces a novel therapeutic approach for MASH by combining ferroptosis targeting with insulin-sensitizing agents.

Findings

MASH induction increased liver weight, inflammation, and ferroptosis markers in mice.

Mitoglitazone and proanthocyanidin improved ferroptosis biomarkers and liver health.

Combining the two treatments showed enhanced benefits in reducing MASH progression.

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.

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