A bifunctional inhibitor CYT-1 synergistically suppresses pyroptosis to improve cognitive dysfunction in diabetic...

Diabetic encephalopathy (DE) is a significant complication of diabetes mellitus, primarily characterized by cognitive impairment. Pyroptosis-mediated neuronal pyroptosis is a key factor in diabetes-induced cognitive dysfunction. Research indicates that using NLRP3 inhibitors to block NLRP3 inflammasome activation or employing H₂S to inhibit NF-κB activation can decrease pyroptosis and improve cognitive dysfunction in DE mice. Here, our aim is to design a bifunctional compound that can simultaneously inhibit the activation of NLRP3 and NF-κB to synergistically suppress neuronal pyroptosis for the clinical treatment of DE. This study reports the novel compound CYT-1, which significantly reduces levels of pyroptosis pathway proteins (p-NF-κB, NLRP3, Caspase-1, and GSDMD-N) and inflammatory factors (IL-1β and IL-18) in vitro. CYT-1 markedly increases H₂S concentrations in both the serum and hippocampus of mice with DE. Western blotting and Nissl staining demonstrated that CYT-1 notably decreased pyroptosis-related protein levels and enhanced hippocampal neuron counts in vivo. The findings demonstrate that CYT-1 synergistically inhibits neuronal pyroptosis by concurrently suppressing NF-κB activation and NLRP3 inflammasome activity. This study may provide new ideas for drug research and clinical treatment of DE.