Nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-), and pyrin domain-containing protein 3 (NLRP3) inflammasome and snake venoms/toxins: mechanisms, pathophysiological relevance, and translational perspectives.

Snake envenoming triggers a complex inflammatory response that substantially contributes to local tissue destruction and systemic complications. Among the innate immune pathways implicated in venom-induced injury, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-), and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key sensor-effector platform linking tissue damage, ionic imbalance, reactive oxygen species (ROS), lipid mediators, and cytokine maturation. Experimental studies indicate that crude venoms and isolated snake toxins, including Lys49 and Asp49 phospholipase A2 (PLA2), metalloproteinases, and C-type lectin/C-type lectin-like proteins, can activate NLRP3 inflammasome-dependent signaling, leading to caspase-1 activation, interleukin (IL)-1β release, and, in some settings, pyroptotic cell death. These findings position the NLRP3 inflammasome as a promising adjunctive therapeutic target in snakebite envenoming, although causal evidence remains restricted to selected toxin models and broader validation across venom classes is still required. This review summarizes the current understanding of NLRP3 inflammasome biology in the context of snake venoms and toxins, discusses the molecular mechanisms proposed for inflammasome priming and activation, and highlights unresolved questions relevant to toxinology, immunology, and adjunctive therapy development. Recent literature also places venom-derived molecules within the broader framework of NLRP3 inflammasome modulation, reinforcing the idea that venoms may serve both as drivers of pathology and as sources of pharmacological leads.