Investigating the mechanism of action of the Mongolian Medicine Areca Thirteen Pill (GY-13) in treating major depressive disorder based on integrated pharmacology

Mongolian Medicine Areca Thirteen Pill (GY-13), a traditional Mongolian medicine, is esteemed for its efficacy in treating Heyi disease. Studies indicate its antidepressant effects on depression model rats induced by chronic stress, but the specific plant extracts (PEs) and their targets remain undetermined. Network pharmacology was applied to identify the key target SLC6A4 and crucial PEs in GY-13 for treating major depressive disorder (MDD). Molecular docking techniques were used to validate the binding capabilities between GY-13 components and SLC6A4. Mendelian randomization was employed to confirm SLC6A4 as a genetically predisposed gene to depression. Molecular dynamics simulations supported the binding affinity between SLC6A4 and PEs Kaempferol and Quercetin. Immunohistochemical techniques were used to confirm the down-regulatory effect of GY-13 on SLC6A4 in an animal model. The key target SLC6A4 and critical PEs Kaempferol and Quercetin in GY-13 were identified for MDD treatment. Strong binding affinity between these PEs and SLC6A4 was demonstrated, and the genetic predisposition of SLC6A4 to depression was confirmed. This study elucidates the molecular mechanisms of GY-13 in treating MDD, highlighting the importance of SLC6A4 and specific PEs Kaempferol and Quercetin in its therapeutic effects.