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

Keting Liu,1,2 Zemin He,3 Lihao Zhang,2 Yong-ming Wu,2 Li Xiao4 1Department of Neurology, Chengdu Seventh People’s Hospital, Affiliated Cancer Hospital of Chengdu Medical College, Chengdu, Sichuan, 610213, People’s Republic of China; 2Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, People’s Republic of China; 3Department of Thoracic Surgery, The First People’s Hospital of Shuangliu District, Chendu, Sichuan Province, People’s Republic of China; 4Department of Human Anatomy, Aging Mechanisms and Interventions Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, Sichuan Province, 610500,People’s Republic of ChinaCorrespondence: Li Xiao, Department of Human Anatomy, Aging Mechanisms and Interventions Key Laboratory of Sichuan Province, Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu, Sichuan Province, 610500, People’s Republic of China, Email [email protected]: 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.Keywords: Parkinson’s disease, NLRP3 inflammasome, neuroinflammation, pyroptosis, α-synuclein, therapeutic targets