Insulin resistance and neuroinflammation play crucial roles in the progression of cognitive impairment following Type 2 Diabetes Mellitus (T2DM), however, current mainstream therapies primarily focus on glycemic control, and the precise molecular mechanisms and direct targets by which Nuciferine ameliorates brain insulin resistance remain unclear.

Here, we elucidate the neuroprotective effects of Nuciferine in HFD/STZ and ICV/STZ mouse models and in vitro high-glucose-induced HT-22 cells, and demonstrate that it restores cognitive function and neuronal survival by directly binding to the Insulin Receptor (IR), activating the downstream PI3K/AKT pathway, inhibiting GSK3β, and reducing Tau hyperphosphorylation. Integrated with proteomics, molecular docking, and CETSA/cellular assays, we further identify IR as the primary target responsible for these effects, which Nuciferine binds to with high affinity to improve insulin sensitivity and reduce oxidative stress.

This work provides a comprehensive theoretical foundation elucidating the critical role of the IR/PI3K/AKT axis in T2DM-CI and clarifies the direct target basis of Nuciferine. The work entitled “Nuciferine ameliorates cognitive impairment and insulin resistance in T2DM by targeting the insulin receptor and activating PI3K/AKT signaling” was published on Chinese Journal of Natural Medicines (published on July 20, 2026).

DOI: 10.1016/S1875-5364(26)61190-9