Xinyu Li, Huamin Ding, Shuyu Qian, Zhiqi Hou, Guoling Yang, Yulin Ma, Yuan Gao, Yilin Zhang, Tiejun Li
Ischemic stroke (IS), a multifaceted neurodegenerative disorder characterized by neuroinflammation and neuronal damage, is critically linked to the cGAS-STING pathway, a key mediator of neuroinflammatory responses during cerebral ischemia. However, the specific role of the STING agonist 2',3'-cGAMP (cGAMP) in modulating ischemic brain injury remains poorly understood. In this study, we investigated the therapeutic effects of cGAMP in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and in BV2 microglial cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Network pharmacology analysis was further employed to predict potential molecular targets and mechanisms underlying cGAMP's action in IS. To validate these findings, TREM2-specific small interfering RNA (siRNA) was utilized to suppress TREM2 expression, enabling mechanistic exploration of cGAMP's activity. Our results demonstrate that cGAMP exerts neuroprotective effects in IS through a noncanonical STING signaling pathway. Specifically, we reveal that cGAMP enhances microglial/macrophage phagocytic function via TREM2-dependent mechanisms. These findings provide novel insights into the therapeutic potential of cGAMP in IS and identify TREM2 as a promising target for modulating neuroinflammation and neuronal recovery in ischemic stroke.