Schisandrin B alleviates APAP-induced hepatocyte ferroptosis via the GPX4 axis: Insights from human iPSC-derived hepatic organoids and rat models.

BACKGROUND

Acetaminophen (APAP) overdose is a major cause of liver injury, while N-acetylcysteine (NAC), the only approved antidote, has limitations. This study used human iPSC-derived hepatic organoids (iHep-Orgs) and a rat model to evaluate the hepatoprotective and anti-ferroptotic effects of Schisandrin B (Sch B), a bioactive lignan from Schisandra chinensis.

PURPOSE: To investigate whether Sch B protects against APAP-induced liver injury by modulating ferroptosis and related metabolic pathways.

STUDY

DESIGN

A dual-model evaluation system integrating human hepatic organoids and an in vivo rat AILI model.

METHODS

Organoids and rats were exposed to APAP followed by Sch B treatment. Hepatic function, cytokines, MDA, GSH, GPX4/SLC7A11 expression, Fe2+ levels, histology, metabolomics, docking, and molecular dynamics were assessed.

RESULTS

In iHep-Orgs, Sch B improved albumin secretion (p < 0.01), reduced TNF-α, IL-1β, and MDA (p < 0.01), and upregulated GPX4 and SLC7A11 mRNA (p < 0.01). Metabolomics revealed remodeling of GSH, amino acid, and lipid metabolism with ferroptosis-related enrichment. Docking and MD showed stable binding to GPX4 and SLC7A11, with stronger GPX4 affinity. In rats, Sch B lowered ALT/AST (p < 0.01), restored GSH (p < 0.05), reduced MDA (p < 0.01), alleviated histological injury, decreased iron deposition, normalized hepcidin (p < 0.01), and restored transferrin (p < 0.01). GPX4 protein increased significantly (p < 0.01), while SLC7A11 protein remained unchanged.

CONCLUSION

Sch B protects against APAP-induced liver injury by enhancing GPX4 activity, reducing lipid peroxidation, and improving iron homeostasis. The combined organoid-animal approach provides a practical framework for evaluating natural products in AILI.