Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for major depressive disorder

• Identified 21 druggable genes with causal evidence for major depressive disorder via Mendelian randomization. • BTN3A3, CISD1, and PSMB4 showed strong colocalization signals, suggesting shared causal variants. • Gemcitabine, fucose, and isococculidine emerged as potential repurposable drugs, with isococculidine showing the most stable binding to BTN3A3. • Integration of genomics and structural biology provides a framework for prioritizing therapeutic targets in depression.