Cathepsin B Inhibition Attenuates Acute Cerebral Ischemia-Reperfusion Injury and Suppresses Associated Apoptotic and Neuroinflammatory Responses

Abstract Cerebral ischemia-reperfusion injury (CIRI) is driven by cell death and multiple secondary pathological responses, but its key regulatory mechanisms remain incompletely understood. Using a rat middle cerebral artery occlusion/reperfusion model and a PC12 cell oxygen-glucose deprivation/reoxygenation model, we investigated the role of cathepsin B (CTSB) in acute CIRI. CTSB inhibition markedly reduced cerebral infarct volume from 42.6% to 15.2% and restored cell viability from 45.2% to 82.5%. Genetic suppression of CTSB produced a comparable protective effect, further supporting its involvement in ischemia-reperfusion-induced injury. Temporal, spatial, and biochemical analyses further revealed coordinated changes between lysosomal stress and apoptosis-related molecular events during reperfusion, suggesting that these processes are closely associated within the acute injury network. More importantly, the protective effects of CTSB inhibition extended beyond apoptosis, with concurrent attenuation of inflammatory responses, restoration of antioxidant defenses, and preservation of blood-brain barrier integrity. Together, these findings suggest that CTSB may serve as an important regulatory node linking cell death with multiple secondary injury processes and may represent a potential therapeutic target for acute CIRI.