Silibinin alleviates acute liver failure by modulating AKT/GSK3β/Nrf2/GPX4 pathway

Area of Science:

• Hepatology
• Pharmacology
• Molecular Biology

Background:

• Silibinin (Sil) from Silybum marianum shows liver benefits.
• Silibinin meglumine (SM), a water-soluble derivative, has potential for liver fibrosis.
• The precise mechanisms of SM in acute liver failure (ALF) remain unclear.

Purpose of the Study:

• To investigate the protective effects and underlying mechanisms of SM in ALF.
• To elucidate SM's role in modulating key cellular pathways.

Main Methods:

• Established ALF mouse and cell (AML12) models using GalN/LPS.
• Administered SM to mice and cells, assessing mortality, liver pathology, and biochemical markers.
• Analyzed the AKT/GSK3β/Nrf2/GPX4 pathway, utilizing ferroptosis inhibitor and AKT silencing.

Main Results:

• SM significantly reduced mortality and improved liver pathology in ALF mice.
• SM enhanced antioxidant levels (GSH, SOD) and modulated inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10).
• SM activated the Nrf2/GPX4 pathway while inhibiting AKT/GSK3β, demonstrating AKT-dependent protection against oxidative stress and ferroptosis.

Conclusions:

• SM exhibits significant hepatoprotective effects against ALF.
• SM functions by inhibiting inflammation and oxidative stress via the AKT/GSK3β/Nrf2/GPX4 pathway.
• The findings highlight SM as a promising therapeutic agent for ALF.