Gypenoside XLIX Alleviates Diclofenac-Induced Hepatotoxicity via Modulating Akt/NLRP3 Pathway

Area of Science:

• Pharmacology
• Hepatology
• Molecular Biology

Background:

• Drug-induced liver injury (DILI) is a significant clinical problem.
• The protective effects of Gypenoside XLIX (GYP XLIX) against liver injury are not well understood.
• Novel therapeutic strategies are needed to combat DILI.

Purpose of the Study:

• To investigate the hepatoprotective mechanisms of GYP XLIX against diclofenac (DF)-induced liver injury.
• To explore the role of the AKT/NLRP3 pathway in GYP XLIX's protective effects.
• To evaluate GYP XLIX as a potential therapeutic agent for chemical hepatotoxicity.

Main Methods:

• In vivo studies using male Wistar rats and in vitro studies with L02 liver cells.
• Network pharmacology, molecular docking, histopathology (H&E staining), qPCR, enzyme activity assays, and Western blotting.
• Assessment of liver enzymes (ALT, AST, ALP), oxidative stress markers (SOD, GSH, MDA), and inflammatory cytokines.

Main Results:

• GYP XLIX significantly reduced DF-induced liver damage, lowering serum liver enzymes and improving histopathology.
• It enhanced antioxidant capacity and suppressed pro-inflammatory cytokine release.
• GYP XLIX promoted AKT phosphorylation and inhibited NLRP3 inflammasome activation via the AKT/NLRP3 pathway.

Conclusions:

• GYP XLIX demonstrates significant hepatoprotective effects against DF-induced liver injury.
• The mechanism involves antioxidative and anti-inflammatory actions through the AKT/NLRP3 pathway.
• GYP XLIX is a promising multi-target therapeutic candidate for DILI and chemical hepatotoxicity.