Revealing the Antidepressant Mechanism of Rhodiola rosea via Network Pharmacology: Integrated Molecular Docking and Dynamics Simulation Validation

Depression, affecting approximately 300 million people globally, is characterized by low mood, cognitive dysfunction, and neuroendocrine issues. Rhodiola rosea (R. rosea) has shown significant antidepressant activity, but its mechanisms are unclear. This study identified 62 chemical constituents in R. rosea extract, with 21 bioavailable compounds detected by UHPLC-Orbitrap Fusion TMS. A total of 3830 depression-related targets were collected from GeneCards, ChEMBL, DisGeNET, and OMIM, and 290 predicted targets for the orally bioavailable components were obtained from TCMSP, SwissTargetPrediction, and PharmMapper. Venny analysis found 157 core targets and was used to construct a PPI network. KEGG analysis showed these targets enriched in endocrine resistance, lipid and atherosclerosis, and AGE-RAGE signaling pathways. Molecular docking revealed salidroside, davidioside, 3,5-digalloylepicatechin, and kenposide A bound strongly to STAT3, HSP90AA1, ESR1, PRKACA, and EGFR. Molecular dynamics simulations confirmed complex stability. In vitro, R. rosea dose-dependently improved viability of CORT-induced HT-22 cells and reversed CORT-mediated downregulation of TPH2, Ht1b, Ht2a, and 5-HT. Notably, this regulatory effect was abolished by the ESR1 inhibitor fulvestrant, confirming R. rosea protects the serotonergic system via ESR1 in the endocrine resistance pathway. This study demonstrates R. rosea's antidepressant effect through multicomponent, multitarget, multipathway synergy, supporting its clinical use.