Network pharmacology and in vivo validation reveal the protective mechanism of 6-gingerol against diabetic encephalopathy.

Diabetic encephalopathy (DE) is a prevalent and severe neurological complication associated with the advanced stages of type 2 diabetes mellitus (T2DM). Its pathogenesis is multifactorial and not yet fully understood, and currently, there are no effective therapeutic interventions available. 6-Gingerol, a natural phenolic compound derived from ginger, exhibits favorable brain-targeting properties and diverse pharmacological activities, making it a promising candidate for the treatment of DE. In this study, the multi-target mechanism of 6-gingerol in DE was systematically investigated by integrating network pharmacological analysis with in vivo experimental validation. Network pharmacology results identified PPARG (namely PPARγ), mTOR, and ESR1 as key core targets of 6-gingerol, which were primarily enriched in pathways related to inflammatory regulation, amyloid-β metabolism, and neuroprotection. Animal experiments demonstrated that four weeks of 6-gingerol treatment significantly reduced fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG) and body weight, while improving cognitive function in 13-week-old db/db mice. Additionally, 6-gingerol markedly attenuated neuroinflammatory responses and decreased soluble amyloid-β levels in the hippocampus. Notably, partial beneficial effects of 6-gingerol were significantly attenuated by GW9662 (a selective PPARγ antagonist), while pioglitazone (a well-known PPARγ agonist) replicated the neuroprotective effects of 6-gingerol in multiple pathological endpoints. Collectively, these findings imply that 6 - gingerol may exert its protective effect against DE via a multi-target synergistic mechanism in which PPARγ plays a key regulatory role.