Sodium aescinate induces hepatocyte ferroptosis through the Nrf2/PRDX6/GPX4 axis

Area of Science:

• Biochemistry
• Toxicology
• Cell Biology

Background:

• Sodium aescinate (SA), derived from horse chestnut seeds, is clinically used but associated with organ toxicities.
• Previous work indicated SA induces hepatocyte ferroptosis, with partial mitigation by boosting glutathione (GSH) synthesis.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying SA-induced hepatotoxicity.
• To investigate the role of the Nrf2/PRDX6/GPX4 pathway in SA-induced ferroptosis.

Main Methods:

• Hepatocyte cell models were used to study SA's effects on redox homeostasis and ferroptosis.
• Nrf2 overexpression, PRDX6 manipulation, selenium supplementation, and GPX4 inhibition were employed.
• Western blotting, quantitative PCR, and cell viability assays were performed.

Main Results:

• SA disrupted redox balance, increased lipid peroxidation, and induced ferroptosis by suppressing the Nrf2/PRDX6/GPX4 pathway.
• SA reduced Nrf2 transcriptional activity, decreasing PRDX6 and GPX4 expression.
• PRDX6 modulated selenium utilization for GPX4 activity; PRDX6 overexpression or selenium supplementation protected against SA toxicity.
• Nrf2/PRDX6/selenium-mediated protection was abolished by GPX4 inhibition, confirming GPX4's critical role.

Conclusions:

• SA induces ferroptotic liver injury by inhibiting the Nrf2/PRDX6/GPX4 axis, leading to GPX4 deficiency and redox collapse.
• Targeting the Nrf2/PRDX6/GPX4 cascade, particularly enhancing GPX4 activity or selenium levels, offers a potential therapeutic strategy for SA-induced hepatotoxicity.