Knockdown SIRT6 Alleviates Blood-Brain Barrier Disruption after Subarachnoid Hemorrhage through Inhibiting Ferroptosis by Promoting SMARCA2 Acetylation

Ferroptosis has been identified as a mechanism underlying subarachnoid hemorrhage (SAH), attributed to blood-brain barrier (BBB) disruption. This study aimed to explore whether SIRT6 mediates Ferroptosis affecting BBB disruption after SAH and the potential mechanism. Knockdown SIRT6 improved the neural function score in SAH rats, reduced the escape latency, increased the number of entering the target quadrant and the time of staying in the platform quadrant, and inhibited Apoptosis while reducing brain water content and BBB disruption, leading to an improvement in neurological deficits after SAH. Concomitantly, knockdown SIRT6 increased OxyHB-induced brain microvascular endothelial cells (BMECs) viability, inhibited Apoptosis, preserved tight junction proteins (Claudin-3, Occludin, and ZO-1) levels, and decreased adhesion molecules (ICAM-1 and VCAM-1) levels, thereby mitigating endothelial barrier dysfunction. Additionally, knockdown SIRT6 inhibited the OxyHb-induced Ferroptosis in BMECs. Furthermore, Ferroptosis inhibitor ferrostatin 1 reversed the proferroptosis effects of SIRT6 overexpression. Mechanically, SIRT6 knockdown reduced Ferroptosis and endothelial barrier dysfunction after SAH by promoting SMARCA2 acetylation. Our results suggested that knockdown SIRT6 inhibited Ferroptosis by promoting SMARCA2 acetylation, thereby alleviating BBB disruption after SAH. These findings establish a novel SIRT6-SMARCA2 axis governing Ferroptosis in SAH, providing mechanistic insights into BBB protection. Our findings may represent promising strategies for the clinical management of SAH.

SIRT6; SMARCA2; acetylation; blood–brain barrier; ferroptosis; subarachnoid hemorrhage.