Matrine disrupts Nrf2/GPX4 antioxidant system and promotes hepatocyte ferroptosis

Area of Science:

• Biochemistry
• Toxicology
• Cell Biology

Background:

• Matrine (MT), an alkaloid from Sophora flavescens, has diverse bioactivities but raises clinical toxicity concerns.
• Understanding the mechanisms of Matrine-induced liver injury is crucial for safe clinical application.

Purpose of the Study:

• To investigate the role of ferroptosis in Matrine-induced liver injury.
• To elucidate the underlying mechanisms involving antioxidant pathways and iron homeostasis.

Main Methods:

• Assessing pathological changes in liver tissues and L02 cell viability.
• Measuring levels of oxidative stress markers (SOD, GSH, MDA, ROS) and lipid peroxidation.
• Analyzing iron homeostasis and protein expression of key ferroptosis-related factors (FTH, Nrf2, xCT, GPX4, HO-1, FSP1, TRF1, DMT1).
• Evaluating the protective effects of ferroptosis inhibitors, Nrf2 agonists, and selenium supplementation.

Main Results:

• Matrine induced significant liver tissue damage and reduced L02 cell viability.
• Matrine disrupted antioxidant balance, increasing oxidative stress and lipid peroxidation, indicative of ferroptosis.
• Matrine altered iron homeostasis and modulated key protein levels associated with ferroptosis, including downregulation of the Nrf2/GPX4 antioxidant system.
• Ferroptosis inhibitors, Nrf2 agonists, and selenium supplementation mitigated Matrine's cytotoxic effects.

Conclusions:

• Matrine triggers hepatocyte ferroptosis by inhibiting the Nrf2/GPX4 antioxidant system.
• Targeting ferroptosis pathways offers a potential therapeutic strategy for Matrine-induced liver toxicity.