Overexpressed CD73 attenuates GSDMD-mediated astrocyte pyroptosis induced by cerebral ischemia-reperfusion injury through the A2B/NF-κB pathway.

Ischemic stroke, resulting from the blockage or narrowing of cerebral vessels, causes brain tissue damage due to ischemia and hypoxia. Although reperfusion therapy is essential to restore blood flow, it may also result in reperfusion injury, causing secondary damage through mechanisms like oxidative stress, inflammation, and excitotoxicity. These effects significantly impact astrocytes, neurons, and endothelial cells, aggravating brain injury and disrupting the blood-brain barrier. CD73, an ectoenzyme that regulates adenosine production through ATP hydrolysis, plays a critical role in purinergic signaling and neuroprotection. During ischemic stroke, CD73 expression is dynamically regulated in response to ischemia and inflammation. It catalyzes the conversion of AMP to adenosine, which activates adenosine receptors to exert neuroprotective effects. Targeting the CD73-adenosine pathway presents a potential therapeutic strategy for mitigating ischemic stroke damage. Pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasomes like NLRP3 and caspases, plays a significant role in cerebral ischemia-reperfusion injury. Astrocytes, the most abundant CNS cells, contribute to both neuroprotection and injury, with pyroptosis exacerbating inflammation and brain damage. Regulating astrocyte pyroptosis is a promising therapeutic target. Our study investigates CD73's role in regulating astrocyte pyroptosis during ischemia-reperfusion injury. Using CD73 knockout mice and overexpression models, along with in vitro oxygen-glucose deprivation/reperfusion experiments, we found that CD73 overexpression reduces GSDMD-mediated astrocyte pyroptosis via the A2B/NF-κB pathway. These findings offer a novel approach to reducing neuroinflammation, protecting astrocytes, and improving outcomes in ischemic stroke.