Quercetin: A Promising Therapy for Diabetic Encephalopathy through Inhibition of Hippocampal Ferroptosis

The pathophysiology of diabetic encephalopathy (DE), a significant diabetes-related pathological complication of the central nervous system, is poorly understood. Ferroptosis is an iron-dependent regulated necrotic cell death process that mediates the development of neurodegenerative and diabetes-related lesions. Quercetin (QE) has anti-ferroptotic effects in various other diseases. Quercetin (QE) exerts anti-ferroptotic effects in various diseases. However, the roles of ferroptosis in DE and the potential anti-ferroptotic mechanisms of QE are unclear. This study aimed to investigate if quercetin can ameliorate DE by inhibiting ferroptosis and to elucidate the potential anti-ferroptotic mechanisms of QE, thus providing a new perspective on the pathogenesis and prevention of DE. The spontaneously type 2 diabetic Goto-Kakizak rats and high glucose (HG)-induced PC12 cells were used as animal and in vitro models, respectively. The Morris water maze test was performed to evaluate the cognition of rats. Pathological damage was examined using hematoxylin and eosin staining. Mitochondrial damage was assessed using transmission electron microscopy. Lipid peroxidation was evaluated by examining the levels of malondialdehyde, superoxide dismutase, and glutathione. Additionally, the contents of iron ions were quantified. Immunofluorescence and western blotting were carried out to poke the protein levels. Network pharmacology analysis was conducted to construct a protein-protein interaction network for the therapeutic targets of QE in DE. Additionally, molecular docking and cell thermostability displacement experiments were performed to examine the target of QE. QE alleviated cognitive impairment, decreased lipid peroxidation and iron deposition in the hippocampus, and upregulated the Nrf2/HO-1 signaling pathway. HG-induced ferroptosis in PC12 cells resulted in decreased cell viability accompanied by lipid peroxidation and iron deposition. QE mitigated HG-induced ferroptosis by upregulating the Nrf2/HO-1 pathway, which was partially suppressed upon Nrf2 inhibition. Network pharmacology analysis further indicated that the Nrf2/HO-1 signaling pathway is a key target of QE. Molecular docking experiments revealed that QE binds to KEAP1 through four hydrogen bonds. Moreover, QE altered the thermostability of KEAP1. These results indicated that QE inhibits ferroptosis in the hippocampal neurons by binding to KEAP1 and subsequently upregulating the Nrf2/HO-1 signaling pathway.