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Central to the cellular antioxidant defense system is the nuclear factor erythroid 2\u2013related factor 2 (Nrf2)\u2013Kelch-like ECH-associated protein 1 (Keap1) pathway, which mitigates oxidative damage and preserves mitochondrial integrity. Concurrently, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome acts as a key mediator of innate immune responses and has been increasingly implicated in neuroinflammatory cascades leading to neuronal loss in PD. Emerging evidence indicates a mechanistic interplay between the Nrf2\u2013Keap1 axis and the NLRP3 inflammasome, wherein Nrf2 activation not only counteracts oxidative stress but also suppresses NLRP3-mediated inflammatory signaling. A comprehensive overview of the molecular crosstalk between the Nrf2 and NLRP3 pathways in the pathogenesis of PD, with emphasis on how impaired Nrf2 signaling exacerbates NLRP3 inflammasome activation, is provided. The preclinical and clinical findings on pharmacological agents that activate Nrf2 or inhibit NLRP3 as potential neuroprotective strategies in PD are also discussed. A growing body of evidence underscores the dual therapeutic benefit of targeting oxidative stress and inflammation via Nrf2 inducers and NLRP3 inhibitors. Nonetheless, obstacles such as restricted blood\u2013brain barrier permeability, unintended effects, and variable clinical trial outcomes hinder the application of these findings in clinical settings. The advancement of disease-modifying therapies for PD hinges on continuous research aimed at deepening the mechanistic understanding of the Nrf2\u2013NLRP3 axis and refining pharmacological strategies.<\/jats:p>","DOI":"10.1007\/s12035-025-05389-0","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T02:53:05Z","timestamp":1763607185000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Nrf2\u2013Keap1 Pathway and NLRP3 Inflammasome in Parkinson\u2019s Disease: Mechanistic Crosstalk and Therapeutic Implications"],"prefix":"10.1007","volume":"63","author":[{"given":"Ridhi","family":"Jain","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8106-9066","authenticated-orcid":false,"given":"Lalitkumar","family":"Vora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Nathiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7066-7706","authenticated-orcid":false,"given":"Dharmendra Kumar","family":"Khatri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"5389_CR1","doi-asserted-by":"publisher","unstructured":"GBD 2016 Neurology Collaborators. 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