The NLRP3-α-Synuclein Circuit: A Core Driver and Therapeutic Target in Parkinson's Disease

The neuroinflammatory mechanisms underlying Parkinson's disease (PD) have evolved from a view of localized central events to a systemic network perspective involving "brain-periphery" interactions. The NLRP3 inflammasome, as a core component of the innate immune system, plays a pivotal role within this network. This review aims to systematically elucidate NLRP3's multifaceted roles in PD: First, it delves into the "self-amplifying" vicious cycle between α-synuclein pathology and NLRP3 activation, supports the hypothesis that this cycle may serve as a core engine. Second, it transcends central nervous system limitations to systematically examine how the central-peripheral immune interaction network-comprising gut microbiota and peripheral immune cells-regulates this cycle. Third, it objectively evaluates the potential and current limitations of NLRP3 pathway-associated molecules as biomarkers for disease diagnosis and progression monitoring. Fourth, it comprehensively reviews therapeutic strategies targeting NLRP3 and critically examines key challenges in their clinical translation. This paper provides an integrated perspective for understanding PD as a systemic inflammatory disease and offers a theoretical framework for future biomarker development and precision treatment strategies based on this pathway.