STAT6 Targets the Autophagy Pathway to Regulate Microglial Senescence in Cognitive Impairment Caused by Cerebral Small-Vessel Disease.

Cerebral small-vessel disease (CSVD) represents a major etiology of vascular cognitive impairment (VCI), driven by pathological processes such as cellular senescence and neuroinflammation. Among these, microglia-the brain's specialized immune cells-play a key role in driving neuroinflammation through their senescence, thereby exacerbating cognitive dysfunction. Although signal transducer and activator of transcription 6 (STAT6) activation has been implicated in alleviating neuroinflammation and cognitive deficits in CSVD, the underlying mechanisms remain unclear. This study sought to elucidate the roles of STAT6 and autophagy in the process of microglial senescence induced by CSVD. Using stroke-prone renovascular hypertensive rats (RHRSP) and chronic hypoxia-treated BV2 cells to assess cognitive function, microglial senescence, and autophagy, we observed that phosphorylation-mediated STAT6 activation significantly suppressed microglial senescence. Mechanistically, we found that phosphorylated STAT6 (pSTAT6) enhanced autophagy, which reduced the burden of senescent microglia and thereby ameliorated CSVD-induced VCI. These findings provide insights into the potential of targeting the STAT6 pathway in VCI associated with CSVD.