Purinergic Signalling in Snakebite Envenomation: Mechanistic Insights, Therapeutic Targets and Future Perspectives

Snakebite envenomation is a major neglected tropical disease associated with substantial morbidity and mortality. Its pathophysiology involves complex interactions between venom components and host responses, leading to inflammation, tissue damage, and systemic alterations. Purinergic signalling has emerged as an important mechanistic pathway underlying these processes. This narrative review was based on a comprehensive literature search of PubMed, Scopus, and Web of Science, focusing on purinergic signalling, snake venoms, inflammasome activation, extracellular nucleotide metabolism, and adjunct therapeutic strategies. Extracellular ATP, acting as a damage-associated molecular pattern (DAMP), activates purinergic receptors and amplifies inflammatory cascades, vascular dysfunction, and cell death pathways. CD39 and CD73 regulate extracellular nucleotide metabolism and generate adenosine, which exerts immunomodulatory and vascular effects. Venom-derived nucleotide-hydrolysing enzymes may also directly modulate host purinergic signalling, supporting an integrated network of host- and venom-derived mechanisms. Purinergic signalling represents a promising mechanistic target for adjunct therapy in snakebite envenomation; however, the temporal dynamics, efficacy, and safety of purinergic-targeted interventions require further preclinical and clinical validation.