<p>Huntington’s disease (HD) is a progressive neurodegenerative disorder in which neuroinflammation, oxidative stress, and mitochondrial dysfunction are increasingly recognized as important contributors to neuronal vulnerability. Recent evidence indicates that the ATP-gated P2X7 receptor (P2X7R) may participate in coordinating several of these pathological processes. Under conditions of cellular stress, elevated extracellular ATP can promote sustained activation of P2X7R, leading to Ca²⁺ influx, mitochondrial depolarization, and enhanced production of reactive oxygen species (ROS), in part through NADPH oxidase-dependent mechanisms. This oxidative environment is associated with lipid peroxidation and the generation of electrophilic aldehydes, such as 4-hydroxynonenal and malondialdehyde, which have the potential to influence chromatin organization and disrupt histone modifications, thereby contributing to altered transcriptional regulation. In parallel, activation of P2X7R in microglia has been linked to NLRP3 inflammasome activation and the release of pro-inflammatory cytokines, including IL-1β and IL-18, which may further exacerbate neuroinflammatory signaling. Together, these observations support the hypothesis of a P2X7-redox-lipid-epigenetic axis that could contribute to neuronal susceptibility and striatal pathology in HD. Preclinical studies suggest that inhibition of P2X7R can attenuate neuroinflammation, improve mitochondrial function, and partially ameliorate behavioral deficits in experimental models. In addition, the development of brain-penetrant P2X7R antagonists and P2X7-specific PET tracers provides emerging opportunities for translational research, biomarker development, and therapeutic monitoring. Overall, P2X7R represents a promising, though still exploratory, therapeutic target in HD.</p> Graphical abstract