Multi-Method Investigation of Icariin's Effects on Diabetic Cognitive Impairment: From Network Prediction to Experimental Confirmation.

Introduction: Neuroinflammation plays a pivotal role in diabetes-associated cognitive dysfunction. Icariin (ICA), a bioactive flavonoid from Epimedium, shows neuroprotective potential, though its mechanism remains unclear.

Methods: Potential ICA targets and diabetic cognitive impairment-related genes were identified through database mining. A protein-protein interaction network was constructed (STRING database) and analyzed (Cytoscape) to identify hub genes. Molecular docking and dynamics simulations validated key targets, followed by in vitro validation using high glucose-induced HT22 cells.

Results: Network pharmacology suggested ICA's neuroprotection involves MAPK pathway modulation and anti-inflammatory effects. In vitro studies confirmed ICA suppressed pro-inflammatory cytokine release and regulated MAPK signaling.

Discussion: ICA's neuroprotection aligns with known flavonoid anti-inflammatory properties. However, limitations include single-cell line use and potentially non-physiological concentrations. Future studies should assess ICA in diabetic animal models, blood-brain barrier penetration, and synergy with antidiabetic drugs.

Conclusion: ICA protects HT22 cells from high glucose-induced damage via MAPK signaling and reduces inflammation, suggesting therapeutic potential for diabetic cognitive impairment. Further in vivo validation is warranted.