Quercetin alleviates liver injury in Wilson's disease by inhibiting ferroptosis

Wilson's disease (WD) is characterized by pathological copper accumulation, primarily driving liver injury. While ferroptosis is implicated in metal toxicity, its role in WD and the therapeutic potential of Quercetin (QUE) remain largely unexplored.

This study aimed to systematically evaluate the therapeutic potential of QUE in a WD model and elucidate its underlying mechanisms, with a specific focus on the ferroptotic pathway.

The efficacy and mechanisms of QUE were investigated using both in vivo and in vitro WD models. Hepatic injury was assessed via histopathology, transmission electron microscopy, and serum biochemistry. Ferroptosis was evaluated by measuring iron content, lipid peroxidation, glutathione metabolism, reactive oxygen species, and mitochondrial membrane potential (using the JC-1 probe). Lipidomics analysis was employed to delineate QUE's impact on lipid metabolism. The central role of the ACSL4/LPCAT3/ALOX15 signaling pathway and QUE's intervention were validated through ACSL4 overexpression experiments, complemented by molecular docking, molecular dynamics simulations, cellular thermal shift assay, surface plasmon resonance, RT-qPCR, Western blotting, and immunofluorescence.

QUE treatment significantly alleviated liver injury, iron overload, oxidative stress, lipid peroxidation, and mitochondrial dysfunction. Lipidomics revealed that QUE effectively reversed the aberrant accumulation of glycerolipids and restored glycerophospholipid metabolic homeostasis, indicating suppression of ferroptosis.. Mechanistically, QUE was confirmed to directly bind to ACSL4 and inhibit the ACSL4/LPCAT3/ALOX15 signaling pathway, thereby blocking ferroptosis.

QUE alleviates phospholipid peroxidation by inhibiting the ACSL4/LPCAT3/ALOX15 signaling pathway and exerts a multi-target effect against ferroptosis and liver injury by collaboratively remodeling iron homeostasis, restoring the antioxidant defense system, and protecting mitochondrial function.