RNA modification by ALKBH5 may protect the heart from injury after blood flow loss and return by stopping iron-related cell death through FSP1

ALKBH5 expression was significantly downregulated during myocardial ischemia/reperfusion injury, resulting in global RNA m6A hypermethylation.

• Overexpression of ALKBH5 improved cardiac function and reduced infarct size in mouse models of ischemia/reperfusion injury.
• ALKBH5 enhances cell viability and preserves mitochondrial membrane potential in cardiomyocytes under hypoxic conditions.
• ALKBH5 directly binds to and demethylates m6A modifications on the mRNA of ferroptosis suppressor protein 1 (FSP1), increasing its stability and expression.
• The upregulation of FSP1 is associated with the inhibition of ferroptosis, evidenced by decreased lipid peroxidation and reactive oxygen species accumulation.
• The protective effects of ALKBH5 were mimicked by the ferroptosis inhibitor ferrostatin-1 and negated by FSP1 knockdown.

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