Integrated clinical and computational data-based repurposing of econazole as a novel autophagic activator in ULK1-related Parkinson disease

mutant mouse models. Notably, its efficacy was dependent on functional autophagy, as autophagy inhibition abrogated its beneficial effects. Mechanistically, econazole activated ULK1, enhanced autolysosome formation, and promoted clearance of SNCA aggregates. Mouse brain microarray analysis indicated that econazole-activated ULK1 suppresses MAP3K12/DLK-MAPK8/JNK-MAPK9/JNK2-mediated neuronal apoptosis. Further phosphoproteomic profiling uncovered a novel ULK1-HSPA8/Hsc70 interaction that promotes LAMP1 and LAMP2 activation and enhances lysosomal function. This ULK1-HSPA8 complex additionally activated the BECN1 (beclin 1) complex to facilitate autophagosome formation. Together, our findings highlight a clinical data-guided drug repurposing approach that identifies econazole as a potent autophagy activator with therapeutic efficacy in ULK1-linked PD models, opening new avenues for PD treatment.