{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:06:54Z","timestamp":1790204814051,"version":"4.1.0"},"reference-count":91,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis.<\/jats:p>","DOI":"10.3390\/nu18091392","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:43:51Z","timestamp":1777448631000},"page":"1392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6857-3927","authenticated-orcid":false,"given":"Rafail C.","family":"Christodoulou","sequence":"first","affiliation":[{"name":"Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-3247","authenticated-orcid":false,"given":"Laura","family":"Lorentzen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Kean University, Union, NJ 07083, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-2759","authenticated-orcid":false,"given":"Daniel","family":"Eller","sequence":"additional","affiliation":[{"name":"Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evros","family":"Vassiliou","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Kean University, Union, NJ 07083, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100944","DOI":"10.1016\/j.jlr.2025.100944","article-title":"The Role of Fatty Acids in Neurodegenerative Diseases: Mechanistic Insights and Therapeutic Strategies","volume":"66","author":"Yang","year":"2025","journal-title":"J. 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