Depression is a common complication in Chronic Kidney Disease (CKD) that significantly impacts patient prognosis. Modified Danggui-Shaoyao-San (MDSS), an optimized version of the traditional Chinese formula Danggui-Shaoyao-San (DSS), has been developed for depression management. This study aimed to assess the clinical efficacy and safety of MDSS in treating depression in CKD patients and to explore its underlying molecular mechanisms using pharmacological analysis and molecular docking. A total of 62 patients were randomly assigned to a treatment group receiving MDSS or a control group receiving placebo. Depression severity was evaluated using the Hamilton Depression Scale, with the primary outcomes being improvement in depressive symptoms and effects on liver and kidney function and electrolyte balance. Core compounds and potential targets of MDSS were identified through the TCMSP database, while CKD- and depression-related molecular targets were obtained from GeneCards, OMIM, and DisGeNET databases. A protein–protein interaction (PPI) network was constructed using the STRING database, and key targets were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Molecular docking was performed to validate the interactions between major active compounds and target proteins. Clinically, patients treated with MDSS showed significant improvement in depressive symptoms without notable adverse effects. Network pharmacology revealed a compound-target network comprising 47 compounds and 69 corresponding targets. GO enrichment analysis identified 844 significant terms, and KEGG pathway analysis highlighted 254 relevant signaling pathways. Molecular docking confirmed strong binding affinities between the top active compounds and four key target proteins. This study provides preliminary evidence supporting the effectiveness of MDSS in alleviating depression in CKD patients and highlights its multi-compound, multi-target pharmacological characteristics.
