Capg Aggravates Neuroinflammatory Injury, Oxidative Stress, and Glial Activation After Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) causes early brain injury characterized by oxidative stress and neuroinflammation, but the molecular mediators linking these processes remain unclear. We aimed to identify SAH-related biomarkers and determine the functional role of Capg in secondary brain injury. Public transcriptomic datasets were integrated, and LASSO, SVM-RFE, random forest, and SHAP analyses were used to prioritize candidate genes. Selected genes were validated in a mouse SAH model. The effects of Capg silencing were examined in vivo and in OxyHb-stimulated BV2 cells and primary mouse astrocytes by assessing neurological function, brain edema, blood-brain barrier disruption, glial activation, inflammatory mediators, oxidative stress, ferroptosis-related markers, and mitochondrial injury-associated proteins. CAPG, DSP, and PHGDH were identified as candidate SAH-related genes, with CAPG showing prominent upregulation. In mice, Capg silencing improved neurological function, reduced brain edema and blood-brain barrier permeability, and attenuated glial activation and neuronal injury. Capg knockdown also reduced IL-1β, IL-6, TNF-α, and IL-18, restored IL-10 expression, and alleviated oxidative stress and ferroptosis-associated alterations, as indicated by increased GPX4 and SOD1 and decreased ACSL4 expression. In OxyHb-stimulated BV2 cells, Capg silencing reduced BAX, tBID, BAK, and cleaved caspase-1 expression, supporting an association between Capg and mitochondrial injury-related inflammatory signaling. Capg is associated with oxidative stress, neuroinflammation, mitochondrial injury-related signaling, and cytokine release after SAH. Targeting Capg may help limit secondary brain injury, although its direct downstream mechanisms require further validation.