This review links disrupted lipid metabolism—altered cholesterol trafficking, sphingolipid/ceramide pathways, and phospholipid remodeling—to neuroinflammation and cell-type–specific metabolic shifts that increase neuronal vulnerability, and it outlines therapeutic approaches (ApoE modulation,…

Provides actionable, translational targets and biomarker strategies tied to inflammation and membrane/lysosomal-related vulnerability that are directly relevant to Parkinson’s therapeutic discovery, despite being a review rather than new primary data.

Lipid metabolism plays a crucial role in maintaining brain homeostasis, affecting energy balance, membrane structure, and signaling pathways essential for neuronal and glial health. Disruption of lipid pathways is linked to neuroinflammation and the progression of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as aging. Changes in cholesterol trafficking, sphingolipid and ceramide metabolism, and phospholipid remodeling can compromise synaptic membrane integrity and signaling, thereby increasing oxidative stress and inflammatory responses. Advanced techniques such as single-cell RNA sequencing (scRNA-seq) and single-nucleus transcriptomics have revealed specific alterations in lipid metabolism across different cell types, indicating a metabolic shift that enhances microglial activation and astrocytic reactivity. This lipid dysregulation contributes to a cycle that heightens neuronal vulnerability. Lipid rafts also facilitate receptor-mediated signaling, tying lipid imbalances to immune activation. Consequently, therapeutic strategies targeting lipid pathways are gaining traction, including modulating apolipoprotein E, inhibiting ceramide synthesis, and supplementing fatty acids to enhance membrane fluidity. Moreover, lipidomics helps identify unique lipid signatures that could serve as biomarkers for early diagnosis and treatment monitoring. Understanding the connection between lipid metabolism, neuroinflammation, and neurodegeneration offers valuable insights for developing targeted interventions in neurodegenerative diseases.