Empagliflozin mitigates methotrexate-induced hepatotoxicity: Targeting ASK-1/JNK/Caspase-3 pathway

Area of Science:

• Pharmacology
• Hepatology
• Toxicology

Background:

• Methotrexate (MTX) is a widely used drug, but its clinical utility is limited by dose-dependent hepatotoxicity.
• Developing strategies to mitigate MTX-induced liver injury is crucial for patient safety and treatment efficacy.

Purpose of the Study:

• To investigate the protective effects of empagliflozin (Empa) against MTX-induced hepatotoxicity in a mouse model.
• To elucidate the underlying mechanisms of Empa's hepatoprotective action.

Main Methods:

• Adult male albino mice were pre-treated with Empa (10 or 25 mg/kg/d) for 6 days before a single MTX injection.
• Evaluated liver function via serum enzyme levels (transaminases, ALP, GGT, albumin).
• Assessed oxidative stress markers, inflammatory cytokines, apoptosis-related proteins, and NF-κB expression in hepatic tissues.
• Histopathological and transmission electron microscopy analyses were performed.

Main Results:

• Empa significantly ameliorated MTX-induced liver damage, normalizing serum liver enzymes and albumin levels.
• Empa restored the oxidant/antioxidant balance by reducing MDA and nitrite/nitrate, and increasing GSH and SOD activity.
• Empa suppressed key inflammatory mediators (TNF-α, IL-6), apoptosis markers (ASK1, JNK, Bax, Caspase-3), and NF-κB activation.
• Empa increased anti-inflammatory IL-10 levels and confirmed protective effects via histopathology.

Conclusions:

• Empagliflozin demonstrates significant hepatoprotective effects against MTX-induced liver injury in mice.
• Empa's mechanism involves mitigating oxidative stress, suppressing inflammation, and inhibiting apoptosis pathways.
• Empa shows potential as an adjuvant therapy to prevent MTX-induced hepatotoxicity, warranting further clinical investigation.