Parkinson's disease (PD) is increasingly conceptualized as a disorder of disrupted neuroimmune integration rather than isolated dopaminergic degeneration. Among innate immune mediators, the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a central, stress-responsive signalling platform within the degenerating nigrostriatal system. This review synthesizes evidence positioning NLRP3 not as an autonomous inflammatory switch, but as a dynamic convergence node embedded within interconnected regulatory networks. Beyond canonical priming, activation licensing, post-translational regulation, and resolution, we highlight how inflammasome competence is governed by interconnected mechanisms controlling priming set points, activation licensing, proteostatic persistence, and endogenous resolution. Crucially, upstream mechanisms, including dopaminergic signalling, PINK1-Parkin-mediated mitophagy, autophagy-lysosomal clearance, redox regulators such as Nrf2, nucleocytoplasmic transport pathways, and lipid signalling collectively dictate inflammasome responsiveness, activation thresholds, and resolution capacity. Dysregulation across these axes stabilizes chronic neuroinflammatory amplification and profoundly reduces the resilience of vulnerable neuronal circuits. We further evaluate emerging clinical efforts targeting NLRP3, highlighting the translational challenges of achieving sustained central target engagement, optimizing therapeutic timing, and validating CNS-relevant biomarkers. By reframing NLRP3 within a systems-level architecture linking mitochondrial dysfunction, proteostatic failure, and innate immune persistence, this review clarifies critical mechanistic checkpoints and therapeutic opportunities for true disease modification in PD.
