FTO-m6A demethylation in cerebral I/R injury: Dual regulation of cell death and neuroinflammation towards therapeutic translation: A review.

Cerebral ischemia-reperfusion injury (CIRI) is a secondary pathological process accompanied by blood flow recovery after ischemic stroke, with oxidative stress, neuroinflammation, cell death (apoptosis, ferroptosis, pyroptosis), and blood-brain barrier disruption as the core mechanisms, leading to high disability/mortality rates. Fat mass and obesity-associated protein (FTO) mediated n6-methyladenosine (m6A) demethylation plays a key epigenetic regulatory role in CIRI. This review systematically elucidates that FTO regulates the pathological process of CIRI through a dual mechanism: at the level of cell death, FTO inhibits apoptosis through the FTO-m6A-b-cell lymphoma 2 (Bcl-2) axis, alleviates oxidative stress through the FTO-YT521-B homology domain family member 2 (YTHDF2)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, inhibits ferroptosis through pathways such as FTO/ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1)/solute carrier family 7 member 11 (SLC7A11), FTO-fyn proto-oncogene (FYN)-dynamin-related protein 1 (Drp1), and inhibits pyroptosis through the FTO/nuclear factor erythroid 2-related factor 2 (Nrf2)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) axis; at the neuroinflammatory level, FTO suppresses microRNA-155 (miRNA-155) maturation through demethylation of primary miRNA-155 (pri-miRNA-155). Additionally, it inhibits the m6A-YT521-B homology domain family member 1 (YTHDF1)-cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling cascade. Together, these mechanisms attenuate M1 polarization and cytokine storm in microglia. Research has shown that FTO function is disease background dependent, and its targeting specificity is regulated by sequence motifs and cellular microenvironment. Although interventions such as electroacupuncture can exert neuroprotective effects by activating FTO, clinical translation still faces challenges such as insufficient targeting specificity and difficulty in penetrating the blood-brain barrier. In the future, it is necessary to combine single-cell multi-omics and spatiotemporal dynamic analysis to analyze the FTO regulatory network, and develop a cell-selective delivery system to promote the development of novel neuroprotective strategies targeting the FTO-m6A axis.