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Cellular Anti-Apoptotic Effects of Dapagliflozin in Methotrexate-Induced Liver Toxicity: Bax/Bcl-2/Cyt-C/Cas-9/Cas-3

Emine Sarman1, Halil Asci2

  • 1Department of Histology and Embryology, Faculty of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar 03030, Türkiye.

International Journal of Molecular Sciences
|March 14, 2026
PubMed

Insights

Dapagliflozin (DAPA) shows promise in protecting the liver from methotrexate (MTX)-induced injury. This study found DAPA mitigates inflammation and apoptosis, offering a potential adjunct therapy for MTX treatment.

Area of Science:

  • Pharmacology and Toxicology
  • Hepatology
  • Molecular Biology

Background:

  • Methotrexate (MTX) is an effective immunosuppressant but causes liver toxicity via oxidative stress, inflammation, and apoptosis.
  • Dapagliflozin (DAPA), a SGLT2 inhibitor, possesses known antioxidant and anti-inflammatory properties.

Purpose of the Study:

  • To investigate the potential hepatoprotective effects of Dapagliflozin (DAPA) against Methotrexate (MTX)-induced acute liver injury in a rat model.
  • To elucidate the molecular mechanisms underlying DAPA's protective action against MTX hepatotoxicity.

Main Methods:

  • Thirty-two female Wistar albino rats were allocated into four groups: Control, MTX, MTX + DAPA, and DAPA.
  • Liver tissues were analyzed using histological, immunohistochemical, molecular (RT-PCR), and biochemical assays to assess injury, inflammation, apoptosis, and oxidative stress.
  • Key markers assessed included NF-κB, TNF-α, IL-1β, VEGF, Bax, Bcl-2, Cytochrome C, and Caspase family proteins, alongside oxidative stress indices (TOS, TAS, OSI).

Main Results:

  • MTX administration caused significant liver damage, characterized by inflammation, apoptosis, and oxidative stress, with altered expression of NF-κB, TNF-α, IL-1β, Bax, Bcl-2, Cytochrome C, and Caspase proteins.
  • DAPA co-treatment significantly ameliorated MTX-induced hepatotoxicity, restoring liver structure and suppressing inflammatory and apoptotic markers.
  • DAPA normalized VEGF expression, suggesting reduced pathological angiogenesis, and effectively mitigated hepatocellular damage despite minimal impact on MTX-induced weight loss.

Conclusions:

  • Dapagliflozin (DAPA) demonstrates significant hepatoprotective effects against Methotrexate (MTX)-induced liver injury.
  • DAPA exerts its protective action by inhibiting NF-κB/TNF-α/IL-1β-mediated inflammation, modulating apoptosis pathways (Bax/Bcl-2-Cyt-C-Caspase), and regulating VEGF-driven angiogenesis.
  • DAPA represents a promising therapeutic adjunct for mitigating liver toxicity associated with Methotrexate treatment.
Keywords:
NF-κBVEGFacute liver injuryapoptosissodium–glucose cotransporter 2 inhibitor

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