TRPC6-TXNIP-NLRP3 signaling axis is involved in type 2 diabetes-associated cognitive dysfunction and the intervention...

Type 2 diabetes-associated cognitive dysfunction (TDACD) poses a significant global public health challenge. However, the core molecular mechanisms underlying its pathogenesis remain incompletely understood, and the development of effective therapeutic interventions continues to face considerable obstacles. Here, we identify the role of the TRPC6-TXNIP-NLRP3 signaling axis in TDACD and to investigate the protective effects and mechanisms of ginsenoside Rg1 against TDACD. T2DM mice exhibited aberrant TRPC6 activation and calcium dyshomeostasis. CHREBP increased nuclear accumulation, and TXNIP upregulate. Ultimately, triggering neuroinflammatory responses and mitochondrial apoptotic. These changes were characterized by upregulation of NLRP3 inflammasome components, increased caspase-3 activity, and cytochrome c release. However, both TRPC6 knockout and Rg1 administration can improve cognitive dysfunction and neuronal damage. In vitro experiments showed that the TRPC6 inhibitor BI749327 can effectively inhibit TRPC6-TXNIP activation, inhibit NLRP3 inflammasome assembly, and reduce neuronal damage and apoptosis, while maintaining intracellular Ca²⁺ homeostasis and mitochondrial membrane potential. In conclusion, TRPC6-induced calcium overload and the TXNIP-NLRP3 signaling pathway are involved in the development of TDACD. Moreover, the neuroprotective effects of Rg1 against TDACD are associated with inhibition of the TRPC6-TXNIP-NLRP3 signaling axis.