Neuroinflammation has been widely recognized as the primary pathophysiological mechanism underlying ischemic white matter lesions (IWML) in chronic cerebral hypoperfusion (CCH), with microglia serving as the principal effector cells. A2aR, an important adenosine receptor, exhibits a dual role in neuroinflammation by modulating both pro-inflammatory and anti-inflammatory responses, particularly through its regulation of microglial polarization. This study aimed to investigate the specific functions and mechanisms of A2aR in neuroinflammation. The findings revealed that A2aR initially exerted a pro-inflammatory role in the CCH model, transitioning to an anti-inflammatory role in later stages by regulating the phenotypic transformation of microglia. Further analyses using CoIP-MS, in situ proximity ligation assay, Alphafold protein structure prediction, [