Adenosine A2A Receptors Mediate Resveratrol-Induced Nrf2 Activation and Cytoprotection Against Oxidative Stress in HeLa Cells

Background/Objectives: Oxidative stress is a major contributor to cellular injury in many pathological conditions, including neurodegenerative disorders. Resveratrol, a natural polyphenol with antioxidant properties, has been proposed as a cytoprotective compound, although the molecular mechanisms underlying its effects remain incompletely understood. Here, we investigated whether the protective action of resveratrol against hydrogen peroxide-induced oxidative stress is mediated by adenosine receptor signalling and activation of the Nrf2 pathway in HeLa cells. Methods: Cells were treated with resveratrol alone or in combination with selective adenosine receptor antagonists and oxidant challenge, and cell viability, ROS production, receptor involvement, and Nrf2 expression and localization were analyzed. Results: Resveratrol at a non-toxic concentration significantly protected HeLa cells against oxidative damage, reduced ROS accumulation, promoted Nrf2 nuclear translocation and gene expression, and enhanced the gene expression of antioxidant enzymes such as SOD1, catalase, HO-1, and NQO1. Pharmacological blockade of the A2A receptor prevented this protective effect, whereas the inhibition of A1 and A3 receptors enhanced it and avoided the increased SOD1, catalase, HO-1, and NQO1 gene expression promoted by resveratrol alone. Moreover, A2A antagonism was associated with reduced PKA levels, consistent with the involvement of the cAMP/PKA signalling axis. Conclusions: Taken together, these observations support a model in which adenosine A2A receptor signalling contributes to resveratrol-associated cytoprotection and Nrf2 activation in a human non-neuronal cell model. Our findings therefore provide mechanistic insight into resveratrol–adenosine receptor interactions and generate hypotheses to be tested in disease-relevant neuronal systems.