Nervonic Acid from Malania oleifera Reverses Parkinson's Disease by Regulating Oxidative Stress, Neuroinflammation, and Gut Microbiota.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by oxidative stress and neuroinflammation. While nervonic acid (NA) is recognized as an essential component of myelin sphingolipids, its specific therapeutic mechanisms in PD have not been thoroughly elucidated. In this study, we investigated the neuroprotective potential of NA derived from Malania oleifera and elucidated its underlying multimechanistic effect. We demonstrated that NA targets the core drivers of neuronal injury by restoring PTEN-induced kinase 1-Parkin-mediated mitophagy to alleviate mitochondrial dysfunction and oxidative stress. Concurrently, NA reprograms microglia from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, thereby inhibiting cytokine secretion and resolving neuroinflammation. Beyond these central protective effects, metabolomics analysis revealed that NA serves as a direct biosynthetic precursor for long-chain ceramides, facilitating myelin regeneration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice, these synergistic mechanisms collectively preserved dopaminergic neurons and improved motor function substantially. Furthermore, 16S ribosomal RNA amplicon sequencing revealed an associative remodeling of the gut microbiota, specifically enriching beneficial genera such as Akkermansia. Collectively, this study establishes NA as a potent multitarget therapeutic that concurrently regulates oxidative stress, neuroinflammation, and myelin regeneration to alleviate PD pathology.