Comprehensive lipidomics reveal Rotenone exposure induces redox-driven lipid droplet accumulation, systemic lipidome perturbation and differential metabolic prioritization linked to Parkinson's disease.

With the global increase in pesticide use and an aging population, concerns about neurodegenerative disease risk and brain health are intensifying, particularly as environmental toxicants like rotenone emerge as significant risk factor. Despite the brain unique vulnerability as a lipid-rich organ, the metabolic impact of chronic rotenone exposure, especially on lipid homeostasis, remains poorly defined. Here, we employed Drosophila melanogaster as an established environmental toxicology model to systematically profile lipidome alterations induced by rotenone. Using high-resolution, untargeted Orbitrap HRAMS lipidomics, we uncovered extensive disruption of mitochondrial lipids, including cardiolipins (CL) and phosphatidylethanolamines (PE), alongside major shifts in glycerolipid classes such as diglycerides (DG) and triglycerides (TG). Notably, our findings reveal previously uncharacterized, tissue-specific remodeling of PE and ether-linked PE (PE-O) species, pointing to impaired metabolic crosstalk between mitochondria and peroxisomes, a process essential for cellular redox balance. We also observed a distinct rise in monounsaturated fatty acids and lipid droplet accumulation, accompanied by disrupted coordination of lipid and fatty acid metabolism between brain and peripheral tissues, establishing a novel biomarker axis of environmental lipidome disruption. Targeted intervention with NAC and L-DOPA restored lipid homeostasis and mitochondrial function, highlighting both the systemic risks associated with chronic pesticide exposure and new avenues for therapeutic intervention.