A mechanistic review linking alpha-synuclein, mitochondrial and lysosomal dysfunction to NLRP3 inflammasome activation in PD and summarizing plant natural products that modulate NLRP3 as candidate neuroprotective agents.

Identifies a druggable, inflammation-driven axis (NLRP3) closely tied to core PD pathologies and compiles plant-derived modulators with translational promise, making it a useful roadmap for prioritizing leads and designing preclinical studies.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the pathological accumulation of α-synuclein (α-syn), a key neuronal protein implicated in neuroinflammation and disease progression. The NOD-like receptor protein 3 (NLRP3) inflammasome, a critical component of the innate immune system, serves as a macromolecular sensor for damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Its aberrant activation drives chronic neuroinflammation, which exacerbates PD pathology. This review elucidates the molecular mechanisms underlying NLRP3 inflammasome activation and its intricate relationship with PD, emphasizing the role of α-syn as a DAMP that triggers NLRP3 via Toll-like receptors (TLRs) and mitochondrial dysfunction. The review highlights how mitochondrial impairment and lysosomal disruption amplify NLRP3 activation, creating a vicious cycle of neuroinflammation and neuronal death. Importantly, emerging evidence demonstrates that plant natural products (PNPs) can effectively target the NLRP3 inflammasome pathway, offering a promising avenue for PD therapy. This review not only establishes the NLRP3 inflammasome as a pivotal macromolecular target in PD therapy but also systematically demonstrates, from the perspectives of structural biology, immunology, and translational medicine, the significant value of PNPs as a novel class of precision neuroprotective modulators-thereby laying a theoretical foundation for developing multi-target, low-toxicity therapeutic agents against PD.