VPS35 is a core component of the retromer complex, a heteropentameric cargo-recognition trimer that mediates retrograde transport from endosomes to the trans-Golgi network 1. Beyond canonical trafficking, VPS35 functions as a reactive oxygen species (ROS) sensor through oxidation-sensitive cysteine residues; hydrogen peroxide oxidation of these cysteines triggers retromer dissociation from endosomal membranes and regulates plasma membrane remodeling to control mitochondrial translation and ROS homeostasis 2. VPS35 mutations cause autosomal dominant monogenic Parkinson's disease, accounting for 5-10% of cases 34. VPS35 participates in mitochondrial-derived vesicle biogenesis alongside Parkin and PINK1, linking this trafficking pathway to neurodegeneration 5. In neurons, VPS35 dysregulation contributes to dopaminergic cell death through cell-autonomous mechanisms and endolysosomal dysfunction 6. Recent evidence suggests VPS35 represents a potential therapeutic target in cancer, where modulating its ROS-sensing function confers chemotherapy resistance in ovarian cancer models 2, while VPS35 manipulation may enhance immunotherapy response 7. Overall, VPS35 integrates membrane trafficking with ROS sensing and mitochondrial quality control, making it critical for neuronal homeostasis and a key player in Parkinson's disease pathophysiology.