STAT3 inhibition ameliorates cognitive dysfunction in type 2 diabetes mellitus by modulating astrocytes via Nrf2 pathway activation.

Type 2 diabetes-associated cognitive dysfunction (TDACD) is a debilitating complication characterized by neuroinflammation and oxidative stress, yet its underlying molecular mechanisms remain incompletely understood. The signal transducer and activator of transcription 3 (STAT3) pathway is increasingly implicated in neurodegeneration, but its specific role in TDACD and its interplay with the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant defense system have not been fully elucidated. This study investigated the therapeutic potential of targeting STAT3 in TDACD using both pharmacological inhibition with niclosamide and specific genetic silencing strategies. In a high-fat diet (HFD) plus streptozotocin (STZ)-induced TDACD mouse model, STAT3 inhibition significantly ameliorated cognitive deficits and reduced neuronal pathology, including amyloid-β and phosphorylated Tau accumulation. Mechanistically, inhibition of STAT3 signaling suppressed neuroinflammation and reactive astrogliosis while simultaneously promoting the nuclear translocation of Nrf2 and the expression of downstream antioxidant enzymes. These effects were also reproduced in vitro using primary astrocytes exposed to high glucose. Specific STAT3 knockdown reversed the pro-inflammatory A1 phenotype and restored redox balance in these cells. Crucially, silencing Nrf2 eliminated the protective effects of STAT3 inhibition, suggesting a functional regulatory axis between STAT3 and Nrf2. Collectively, our findings support that STAT3 inhibition ameliorates cognitive dysfunction by disinhibiting the Nrf2 pathway to restore redox homeostasis and shift astrocytes towards a neuroprotective phenotype, highlighting the STAT3-Nrf2 axis as a promising therapeutic target for TDACD.