ALKBH5 mediated RNA N6-methyladenosine demethylation protects against myocardial I/R induced injury via FSP1 dependent inhibition of ferroptosis

In the realm of myocardial ischemia/reperfusion (I/R) injury, the intricate interplay between RNA modifications and cellular responses remains a subject of intense investigation. Here, we elucidate a pivotal role of ALKBH5-mediated RNA N6-methyladenosine (m6A) demethylation in safeguarding against myocardial I/R-induced injury through the inhibition of ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation. Our study unveils a novel mechanism wherein ALKBH5, a member of the AlkB family of dioxygenases, acts as a critical regulator of RNA m6A modification, thereby influencing the susceptibility of cardiomyocytes to I/R injury. Using a combination of in vitro and in vivo models, we demonstrate that ALKBH5 expression is dynamically modulated in response to myocardial I/R insult. Mechanistically, ALKBH5-mediated demethylation of specific RNA transcripts, orchestrated by its catalytic activity, mitigates ferroptosis by regulating the expression of key ferroptosis-related genes. Importantly, we identify ferroptosis-suppressor-protein 1 (FSP1) as a downstream effector of ALKBH5-mediated m6A demethylation, linking the protective effects of ALKBH5 to the inhibition of ferroptosis in cardiomyocytes. Furthermore, our findings highlight the clinical relevance of ALKBH5 in myocardial I/R injury, as evidenced by the exacerbation of cardiac dysfunction and infarct size in ALKBH5-deficient mice subjected to I/R insult. Conversely, overexpression of ALKBH5 confers robust protection against myocardial I/R injury, underscoring its therapeutic potential in the management of ischemic heart disease. Collectively, our study delineates a novel axis involving ALKBH5-mediated RNA m6A demethylation and FSP1-dependent inhibition of ferroptosis as a critical mechanism for cardio protection against myocardial I/R-induced injury. Targeting this axis holds promise for the development of innovative therapeutic strategies aimed at attenuating myocardial I/R injury and improving clinical outcomes in patients with ischemic heart disease.