Astrocytic SIRT3 Alleviates Neuroinflammatory Responses After Cerebral Ischemia/reperfusion by Inhibiting the cGAS-STING Pathway

Ischemic stroke triggers detrimental neuroinflammatory responses where astrocytes play a pivotal role. This study investigates whether Sirtuin 3 (SIRT3), a key cellular regulator, mitigates astrocyte-mediated neuroinflammation by modulating the cGAS-STING pathway. Using in vivo ischemic stroke models and in vitro astrocyte cultures subjected to ischemic-like injury, we demonstrate that SIRT3 expression is significantly suppressed post-injury, coinciding with pronounced activation of the cGAS-STING signaling cascade and elevated release of pro-inflammatory cytokines. Pharmacological activation of SIRT3 or its genetic overexpression effectively reduced cerebral damage, improved neurological outcomes, and suppressed cGAS-STING pathway activation. Conversely, targeted knockdown of cGAS or STING similarly attenuated inflammatory responses. Transcriptomic analysis revealed that SIRT3 overexpression alters genes associated with DNA sensing and innate immune pathways. These findings establish that SIRT3 alleviates post-stroke neuroinflammation in astrocytes by inhibiting the cGAS-STING pathway, highlighting SIRT3 as a promising therapeutic target for ischemic stroke treatment.