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

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