Sitagliptin inhibits neuronal ferroptosis to alleviate cognitive dysfunction by activating Nrf2-SLC7A11-GPX4 axis in diabetic mice.

Diabetic cognitive dysfunction (DCD) is one of the major complications of type 2 diabetes mellitus (T2DM). At present, there is still no clinical consensus on the improvement and treatment of DCD, mainly due to limitations in understanding the pathogenesis and a lack of effective drugs. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, shows potential for alleviating DCD. However, its neuroprotective mechanisms remain inadequately explored. Herein, our findings showed that sitagliptin reduced fasting blood glucose, decreased body weight, lowered insulin resistance, and attenuated levels of inflammatory markers in diabetic mice. Moreover, sitagliptin treatment significantly ameliorated DM-induced disability of learning and memory. Subsequently, we observed that sitagliptin impedes neuronal ferroptosis both in diabetic mice and high glucose combined with palmitic acid (HG + PA)-stimulated primary neurons and PC12 neuronal cells, partly reflected in decreased lipid and intracellular reactive oxygen species (ROS) levels, increased glutathione (GSH) and superoxide dismutase (SOD) levels, reduced malondialdehyde (MDA) content, and elevated expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), compared to the corresponding alterations observed in diabetic mice. Mechanistically, molecular docking and cellular thermal shift assays revealed that sitagliptin directly binds to and enhances the nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Moreover, genetic loss of Nrf2 by transfected Nrf2 siRNA significantly blunted sitagliptin-induced ferroptosis inhibition in primary neurons and PC12 neuronal cells under HG + PA conditions, whereas Nrf2 overexpression further augmented the beneficial effect of sitagliptin on impeding neuronal ferroptosis. These data indicated that sitagliptin regulated Nrf2 expression, which modulated the SLC7A11-GPX4 axis, inhibited neuronal ferroptosis, and finally ameliorated diabetic cognitive dysfunction.