N6-Methyladenosine Demethylase FTO Mitigates Cerebral Ischemia-Reperfusion Injury by Suppressing AQP4 Expression.

AIM: In patients with acute ischemic stroke, reperfusion therapy can compromise the blood-brain barrier, resulting in secondary cerebral ischemia-reperfusion injury (CIRI). This study investigated the involvement of the N6-methyladenosine (m6A) demethylase FTO in the pathogenesis of CIRI and explored the underlying molecular mechanisms.

METHODS

We established a middle cerebral artery occlusion (MCAO) mouse model in vivo and an oxygen-glucose deprivation/reperfusion (OGD/R) model in primary astrocytes in vitro.

RESULTS

FTO expression was significantly downregulated in both the in vivo and in vitro CIRI models. Upregulation of FTO via plasmid transfection significantly attenuated cellular damage and enhanced astrocyte viability. At the molecular level, m6A-modified transcripts were enriched in the MAPK signaling pathway during cerebral ischemia-reperfusion. Notably, Heat Shock Protein Family A (Hsp70) Member 1A (Hspa1a) was identified as a key target. The reduction in FTO expression led to increased m6A methylation levels on Hspa1a mRNA, thereby promoting its degradation. Furthermore, the cellular damage induced by FTO silencing was alleviated by Hspa1a overexpression or the silencing of Aquaporin-4 (AQP4).

CONCLUSIONS

This study demonstrates that FTO mitigates CIRI by stabilizing Hspa1a mRNA, which in turn suppresses AQP4 expression. Consequently, FTO represents a promising therapeutic target for the treatment of ischemic stroke.