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Procyanidin B2 mitigates methotrexate-induced hepatic pyroptosis by suppressing TLR4/NF-κB and caspase-3/GSDME

Juman Alsaab1, Wedad S Sarawi1, Ahlam M Alhusaini1

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh, 11495, Saudi Arabia.

Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association
|February 23, 2025
PubMed

Insights

Procyanidin B2 (PCB2) shows protective effects against methotrexate (MTX)-induced liver damage. PCB2 demonstrated antioxidant, anti-inflammatory, and anti-pyroptosis properties, mitigating MTX toxicity in rats.

Area of Science:

  • Hepatology
  • Pharmacology
  • Toxicology

Background:

  • Methotrexate (MTX) is a vital chemotherapeutic and immunosuppressive drug.
  • MTX-induced hepatotoxicity is a significant clinical concern, even at low doses.
  • Understanding protective agents against MTX liver injury is crucial.

Purpose of the Study:

  • To investigate the potential hepatoprotective effects of procyanidin B2 (PCB2) against MTX-induced liver toxicity.
  • To evaluate the impact of PCB2 on oxidative stress, inflammation, and pyroptosis markers in MTX-treated rats.

Main Methods:

  • Rats were treated with PCB2 (40 mg/kg) or quercetin (positive control, 20 mg/kg) followed by MTX (20 mg/kg) injection.
  • Serum transaminases, hepatic oxidative/antioxidant markers (MDA, GSH, SOD), inflammatory cytokines (TNF-α, IL-1β, IL-6), and key protein expressions (NF-κB, TLR4, caspase-3, GSDME) were analyzed.

Main Results:

  • MTX administration significantly elevated serum transaminases, indicating liver injury.
  • MTX induced hepatic oxidative stress, increased inflammatory cytokines, and upregulated NF-κB, TLR4, caspase-3, and GSDME.
  • PCB2 treatment significantly ameliorated MTX-induced hepatotoxicity by restoring oxidant/antioxidant balance and reducing inflammation and pyroptosis markers.

Conclusions:

  • Procyanidin B2 exhibits significant hepatoprotective effects against methotrexate-induced liver injury in rats.
  • PCB2 demonstrates antioxidant, anti-inflammatory, and anti-pyroptosis activities, suggesting its potential therapeutic role.
  • Further research is warranted to confirm PCB2's efficacy as a protective therapy for MTX hepatotoxicity.
Keywords:
Gasdermin EHepatoxicityInflammationMTXOxidative stressPCB2Pyroptosis

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