Spatial Lipidomics and Transcriptomics Reveal Nicotine-Mediated Restoration of Lipid Homeostasis in Parkinson’s Disease

Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration, and increasing evidence implicates disrupted lipid metabolism as a critical contributor to disease pathogenesis. Although nicotine has been associated with a reduced risk of PD, the mechanisms underlying its neuroprotective effects remain incompletely understood. Here, we investigated whether nicotine protects against PD by modulating brain lipid metabolism. Using 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, we combined behavioral assessments, transcriptomic profiling, and desorption electrospray ionization mass spectrometry imaging to examine the effects of nicotine on motor function, gene expression, and spatial lipid distribution in the brain. Nicotine treatment significantly improved motor performance preserved nigrostriatal dopaminergic neurons, and attenuated neuroinflammatory responses. Spatial lipidomic analysis revealed widespread disturbances in lipid composition within the substantia nigra, striatum, and hippocampus of PD mice, many of which were reversed by nicotine administration. Integrated analysis of transcriptomic and lipidomic data further demonstrated that nicotine reshapes lipid metabolic pathways associated with neuronal survival and inflammatory regulation, leading to restoration of brain lipid homeostasis. Together, these findings provide multimodal evidence that restoration of lipid homeostasis is a key mechanism underlying nicotine-mediated neuroprotection in PD. Our results identify lipid remodeling as a mechanistic link between nicotine exposure and neuroprotection and highlight brain lipid metabolism as a potential therapeutic target for Parkinson's disease.