Mogrol Protects Against Warm Hepatic Ischemia-Reperfusion Injury by Preserving Mitochondrial Function through PI3K/AKT/GSK3β Signaling.
TL;DR
Mogrol mitigates warm HIRI, at least in part, by activating the PI3K/AKT/GSK3β signaling pathway, thus highlighting its potential as a naturally derived candidate for liver protection.
Abstract
Background
Warm hepatic ischemia-reperfusion injury (HIRI) is a common complication of liver surgery that significantly impairs clinical outcomes, and effective therapeutic strategies remain limited. Mogrol is a bioactive component derived from Siraitia grosvenorii that exhibits potent anti-inflammatory and antioxidant properties; however, its role in warm HIRI and the underlying mechanisms remain largely unexplored.
Methods
The effects of Mogrol were investigated using an in vivo warm hepatic I/R model with mice and an in vitro hypoxia/reoxygenation model with AML12 cells. Mogrol was administered with or without the PI3K inhibitor LY294002. Liver function, histopathology, oxidative stress, inflammatory responses, and mitochondrial function were assessed using biochemical assays, fluorescence staining, transmission electron microscopy (TEM), and adenosine triphosphate (ATP) measurements. Transcriptomic analysis, molecular docking, cellular thermal shift assay (CETSA), and western blotting were performed to explore the underlying mechanisms.
Results
Mogrol pretreatment significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, alleviated hepatic necrosis, suppressed oxidative stress and inflammatory responses, restored mitochondrial ultrastructure, stabilized mitochondrial membrane potential (MMP), inhibited mitochondrial permeability transition pore (mPTP) opening, enhanced ATP production, and attenuated mitochondria-mediated apoptosis in both in vivo and in vitro models. These protective effects were partially reversed by LY294002.
Conclusion
Mogrol mitigates warm HIRI, at least in part, by activating the PI3K/AKT/GSK3β signaling pathway, thus highlighting its potential as a naturally derived candidate for liver protection.