ATP-P2X7R-NLRP3 Axis as a Unifying Mechanism of ATP-Induced Cell Death in Degenerative Bone and Cardiovascular Diseases

Abstract: Extracellular Adenosine triphosphate (ATP), acting as both an energy signal and damage-associated molecular pattern (DAMP), plays a critical role in the progression of degenerative bone diseases (DBD) and cardiovascular diseases (CVD). Through activation of purinergic receptors, particularly P2X7, ATP induces a cascade of events leading to ATP-induced cell death (AICD), characterized by calcium influx, mitochondrial dysfunction, oxidative stress, and inflammasome activation, culminating in pyroptosis, apoptosis, and ferroptosis. These processes are implicated in osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and cardiovascular conditions such as myocardial infarction and heart failure. The ATP-P2X7-NLRP3 axis emerges as a shared molecular mechanism linking these diseases, driven by energy imbalance and chronic inflammation. This review explores the molecular mechanisms of AICD in DBD and CVD, evaluates experimental and clinical evidence, and discusses potential therapeutic strategies targeting the ATP–purinergic–mitochondrial axis, offering insights into integrated treatment approaches for both disease types. Keywords: ATP-induced cell death, purinergic signaling, P2X7 receptor, mitochondrial dysfunction, NLRP3 inflammasome, degenerative bone disorders, cardiovascular remodeling