Journal Article Review Epublish 3 citations
PubMed: 40806376 DOI: 10.3390/ijms26157241
Non-Canonical Functions of Adenosine Receptors: Emerging Roles in Metabolism, Immunometabolism, and Epigenetic Regulation.
Int J Mol Sci 26(15)
Authors: Giovanni Pallio, Federica Mannino
Affiliations
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, Via C. Valeria, 98125 Messina, Italy.
- Department of Medicine and Surgery, University of Enna "Kore", Contrada Santa Panasia, 94100 Enna, Italy.
Abstract
Adenosine receptors (ARs) are G protein-coupled receptors that are widely expressed across tissues, traditionally associated with cardiovascular, neurological, and immune regulation. Recent studies, however, have highlighted their non-canonical functions, revealing critical roles in metabolism, immunometabolism, and epigenetic regulation. AR subtypes, particularly A2A and A2B, modulate glucose and lipid metabolism, mitochondrial activity, and energy homeostasis. In immune cells, AR signaling influences metabolic reprogramming and polarization through key regulators such as mTOR, AMPK, and HIF-1α, contributing to immune tolerance or activation depending on the context. Additionally, ARs have been implicated in epigenetic modulation, affecting DNA methylation, histone acetylation, and non-coding RNA expression via metabolite-sensitive mechanisms. Therapeutically, AR-targeting agents are being explored for cancer and chronic inflammatory diseases. While clinical trials with A2A antagonists in oncology show encouraging results, challenges remain due to receptor redundancy, systemic effects, and the need for tissue-specific selectivity. Future strategies involve biased agonism, allosteric modulators, and combination therapies guided by biomarker-based patient stratification. Overall, ARs are emerging as integrative hubs connecting extracellular signals with cellular metabolic and epigenetic machinery. Understanding these non-canonical roles may unlock novel therapeutic opportunities across diverse disease landscapes.
MeSH
Receptors, Purinergic P1, Adenosine, Therapeutics, Tissues