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REVIEW ARTICLE

Lipid metabolism dysregulation in Parkinson’s disease: Mechanistic insights and therapeutic implications

Ming-Ming Wang1,2 ,  Xiao-Min Wen2,3 ,  Hui Dong4,5 ,  Xue-Qin Song4,5 ,  Sheng-Xi Wu2,3* ,  Ye Xi2,3*
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1 The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
2 Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi, China
3 The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi’an, Shaanxi, China
4 Key Laboratory of Clinical Neurology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China
5 Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
Advanced Neurology 2025, 4(4), 31–47; https://doi.org/10.36922/AN025320086
Received: 8 August 2025 | Revised: 4 September 2025 | Accepted: 5 September 2025 | Published online: 16 October 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of nigrostriatal dopaminergic neurons and pathological accumulation of α-synuclein (α-Syn) aggregates. Emerging evidence indicates the important role of lipid metabolism dysregulation in driving these pathological features. As major structural components of brain tissue and critical regulators of neuronal function, lipids are involved in diverse biological processes, including cell membrane formation, intercellular signaling, energy storage, and homeostasis. Their dysregulation directly affects neural functions, such as synaptic transmission, antioxidant defense, and inflammatory modulation. PD is recognized not only as a “proteinopathy” but also as an “organelle communication disorder,” involving dysfunction of membrane contact sites across mitochondria, endoplasmic reticulum, lysosomes, and lipid droplets (LDs)—a process that may constitute an early pathogenic event. It is noteworthy that several proteins mediating LDs–organelle contacts are disease-related factors encoded by mutated genes in inherited neurological and metabolic disorders. Despite the extensive communication between intracellular LDs and other organelles through these contact sites, the systematic integration of lipid metabolism dysregulation into core PD pathogenesis remains elusive. This review provides a comprehensive overview of the mechanisms underlying lipid–organelle interactions in PD pathogenesis, with a specific focus on the triangular interplay among the three core pathological hallmarks: α-Syn aggregation, mitochondrial dysfunction, and neuroinflammation, and their convergence with the lipid metabolic network. By analyzing molecular mechanisms and clinical implications, with particular focus on lipid-related biomarkers and therapeutic strategies targeting organelle communication pathways, this review aims to provide new insights into the role of lipid dyshomeostasis in PD pathogenesis and identify feasible therapeutic targets.

Graphical abstract
Keywords
Parkinson’s disease
Lipid metabolism
Organelle communication
α-Synuclein
Mitochondrial dysfunction
Funding
This work was funded by the Natural Science Foundation of China (82571429 to Y.X., 82221001 to S.W.), the Natural Science Basic Research Program of Shaanxi (2024JC-YBQN-0774 to Y.X.), and the Open Fund of Key Laboratory of Clinical Neurology, Ministry of Education (2025A02 to Y.X.).
Conflict of interest
Sheng-Xi Wu is an Associate Editor of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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Advanced Neurology, Electronic ISSN: 2810-9619 Print ISSN: 3060-8589, Published by AccScience Publishing
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