N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand

•m6A is an endogenous adenosine A3 receptor ligand with higher potency than •Extracellular m6A mainly stems from ribosomal RNA and mRNA •Cytotoxic stimulation induces release via lysosome-mediated catabolism facilitates allergy inflammation About 150 post-transcriptional modifications have been identified in all kingdoms of life. During catabolism, most modified nucleosides are resistant to degradation released into the extracellular space. In this study, we explored physiological role these found that N6-methyladenosine (m6A), widely recognized as epigenetic mark RNA, acts a for human receptor, which it has greater affinity unmodified adenosine. We used structural modeling define amino acids required specific binding receptor. also demonstrated was dynamically response cytotoxic stimuli facilitated type I vivo. Our findings implicate signaling molecule capable activating G protein-coupled receptors (GPCRs) triggering pathophysiological responses, previously unreported property modifications.