Neuroinflammation has been widely recognized as the primary pathophysiological mechanism underlying ischemic white matter lesions (IWML) in chronic cerebral hypoperfusion (CCH). Adenosine A2A receptor (A2aR), an important adenosine receptor, exhibits a dual role in neuroinflammation by modulating both proinflammatory and anti-inflammatory responses. This study aimed to investigate the specific functions and mechanisms of A2aR in neuroinflammation. The findings revealed that A2aR initially exerted a proinflammatory role in the CCH model, transitioning to an anti-inflammatory role in later stages by regulating the phenotypic transformation of microglia. Further analyses using coimmunoprecipitation couple with mass spectrometry, in situ proximity ligation assay, AlphaFold protein structure prediction, [