{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T15:40:19Z","timestamp":1772466019713,"version":"3.50.1"},"reference-count":73,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["NeuroSci"],"abstract":"<jats:p>Background and aim: Alterations in immune signaling have emerged as a key factor contributing to Parkinson\u2019s disease pathophysiology. Increasing evidence also suggests that MASLD and Parkinson\u2019s disease may share common immunological mechanisms. Among these, TLR4 has been linked to immune surveillance processes and inflammatory responses in both the central nervous system and the liver. The aim of our study was to delineate TLR4-mediated immune networks underpinning the molecular overlap between MASLD and Parkinson\u2019s disease. Methods: Disease\u2013disease and gene\u2013disease associations were systematically retrieved from the DisGeNet database to map TLR4-related molecular networks across both conditions. Functional enrichment analyses were subsequently applied to identify biological pathways significantly associated with TLR4, including potential gene\u2013drug interactions. Guided by these results, a scoping review of the literature was undertaken to summarize existing evidence addressing TLR4-dependent mechanisms in MASLD and Parkinson\u2019s disease. Results: DisGeNet analysis indicated 978 shared genes and 39 SNPs shared between both diseases. TLRs, including TLR4-associated coreceptors such as CD14, are among these shared genes. Among these, TLR4 and its missense SNP rs4986791 emerged as key shared immunometabolic nodes linking both diseases. Among the shared SNPs identified in both diseases, we focused on TLR4, where the common variant was rs4986791. Gene set enrichment analysis revealed multiple biological processes associated with cytokine signaling, inflammation, and fibrogenesis. Gene\u2013drug enrichment analysis identified statins and fibrates among the compounds enriched in TLR4-containing networks. Conclusions: These findings support a role for TLR4-associated pathways in linking immunometabolic processes across MASLD and Parkinson\u2019s disease. Disruption of these pathways is associated with aberrant inflammatory regulation, with tissue-specific effects further contributing to the distinct molecular pathology observed in each condition. Consequently, modulation of TLR4 signaling represents a plausible strategy for the development or repositioning of disease-modifying interventions applicable to both conditions.<\/jats:p>","DOI":"10.3390\/neurosci7020028","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T14:06:56Z","timestamp":1772460416000},"page":"28","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TLR4-Mediated Immune Dysfunction Links MASLD and Parkinson\u2019s Disease: Insights from an Omics-Based Network Analysis"],"prefix":"10.3390","volume":"7","author":[{"given":"Christina","family":"Flourou","sequence":"first","affiliation":[{"name":"Medical School, University of Cyprus, Nicosia 2029, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-3837","authenticated-orcid":false,"given":"Nikolaos","family":"Dietis","sequence":"additional","affiliation":[{"name":"Medical School, University of Cyprus, Nicosia 2029, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0463-4321","authenticated-orcid":false,"given":"Sotirios","family":"Tsiordas","sequence":"additional","affiliation":[{"name":"4th Department of Internal Medicine, Medical School, University General Hospital Attikon, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5386-4273","authenticated-orcid":false,"given":"Georgios","family":"Hadjigeorgiou","sequence":"additional","affiliation":[{"name":"Medical School, University of Cyprus, Nicosia 2029, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0413-4028","authenticated-orcid":false,"given":"George D.","family":"Vavougios","sequence":"additional","affiliation":[{"name":"Medical School, University of Cyprus, Nicosia 2029, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.7570\/jomes23052","article-title":"Metabolic dysfunction-associated steatotic liver disease (MASLD): A state-of-the-art review","volume":"32","author":"Chan","year":"2023","journal-title":"J. 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