Downregulation of Nrf2 and upregulation of TXNIP/NLRP3 signaling Induce postoperative cognitive dysfunction via oxidative stress and pyroptosis in the hippocampus.

Postoperative Cognitive Dysfunction (POCD) is a neurocognitive complication after anaesthesia and surgery, with oxidative stress as a key pathological driver. Nuclear factor erythroid-related factor 2 (Nrf2) and Thioredoxin-Interacting Protein (TXNIP) are critical regulators of oxidative stress and inflammation, and TXNIP directly facilitates NLRP3 inflammasome activation. Using an 18-month-old mouse model of POCD established by tibial fracture surgery, we investigated the changes in the expression of TXNIP and the regulatory mechanism of the Nrf2/TXNIP/NLRP3 signaling pathway. Cognitive function was assessed by the Morris water maze test, and hippocampal samples were analyzed for protein levels(Nrf2, TXNIP, and NLRP3 inflammasome-related protein), pro-inflammatory factors (IL-1β and IL-18), Reactive Oxygen Species (ROS), and neuronal apoptosis. Anesthesia/surgery significantly upregulated TXNIP expression. Inhibiting TXNIP with verapamil attenuated oxidative stress, neuronal injury, and NLRP3 inflammasome activation, thereby ameliorating cognitive impairment. Similarly, sulforaphane (SFN)-mediated upregulation of Nrf2 suppressed TXNIP expression, decreased NLRP3 inflammasome-related proteins and pro-inflammatory factors, and alleviated cognitive deficits. These findings demonstrate thatthe Nrf2/TXNIP/NLRP3 axis mediates hippocampal oxidative stress and pyroptosis in POCD pathogenesis, highlighting this pathway as a potential therapeutic target.