{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T02:51:37Z","timestamp":1793328697286,"version":"4.5.0"},"reference-count":186,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T00:00:00Z","timestamp":1767398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and pathological \u03b1-synuclein aggregation. Growing evidence identifies chronic neuroinflammation\u2014particularly NLRP3 inflammasome activation in microglia\u2014as a central driver for PD onset and progression. Misfolded \u03b1-synuclein, mitochondrial dysfunction, and environmental toxins act as endogenous danger signals that prime and activate NLRP3 inflammasome, leading to caspase-1\u2013mediated maturation of IL-1\u03b2 and IL-18 and subsequent pyroptotic cell death. Impaired mitophagy, due to defects in PINK1\/Parkin pathways or receptor-mediated mechanisms, permits accumulation of dysfunctional mitochondria and release DAMPs, thereby amplifying NLRP3 activity. Studies demonstrate that promoting mitophagy or directly inhibiting NLRP3 attenuates neuroinflammation and protects dopaminergic neurons in PD models. Autophagy-inducing compounds, along with NLRP3 inhibitors, demonstrate neuroprotective potential, though their clinical translation remains limited due to poor blood\u2013brain barrier penetration, off-target effects, and insufficient clinical data. Additionally, the context-dependent nature of mitophagy underscores the need for precise therapeutic modulation. This review summarizes current understanding of inflammasome\u2013mitophagy crosstalk in PD, highlights major pharmacological strategies under investigation, and outlines its limitations. Future progress requires development of specific modulators, targeted delivery systems, and robust biomarkers of mitochondrial dynamics and inflammasome activity for slowing PD progression.<\/jats:p>","DOI":"10.3390\/ijms27010486","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T12:38:56Z","timestamp":1767616736000},"page":"486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mitophagy\u2013NLRP3 Inflammasome Crosstalk in Parkinson\u2019s Disease: Pathogenic Mechanisms and Emerging Therapeutic Strategies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2538-9887","authenticated-orcid":false,"given":"Sahabuddin","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tulasi","family":"Pasam","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzana","family":"Afreen","sequence":"additional","affiliation":[{"name":"Independent Researcher, New Haven, CT 06511, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0140-6736(23)01419-8","article-title":"The epidemiology of Parkinson\u2019s disease","volume":"403","author":"Darweesh","year":"2024","journal-title":"Lancet"},{"key":"ref_2","first-page":"101078","article-title":"Disease burden of Parkinson\u2019s disease in China and its provinces from 1990 to 2021: Findings from the global burden of disease study 2021","volume":"46","author":"Xu","year":"2024","journal-title":"Lancet Reg. 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