OBJECTIVE To systematically evaluate the clinical efficacy and safety of CLM in improving post-stroke depression (PSD), providing evidence-based medicine support; and to integrate network pharmacology and molecular docking technology to construct a multi-network model to elucidate its potential pharmacodynamic material basis and mechanism.

METHODS The latest data (up to July 2025) were searched in Chinese and English databases, and randomized controlled trials (RCTs) of CLM for PSD were screened. The Cochrane risk of bias assessment tool and RevMan 5.4 software were used for quality assessment and meta-analysis. Simultaneously, using databases such as TCMSP, SwissTargetPrediction, and GeneCards, the active components and targets of CLM were screened; a herbal medicine-component-target (H-C-T) network was constructed, protein-protein interaction (PPI) network and topology analysis were performed, and GO function and KEGG pathway enrichment analysis were conducted. Molecular docking was then used to verify the binding ability of core components and key targets.

RESULTS The meta-analysis included 26 RCT studies with a total of 2 141 patients. The results showed that, whether CLM was used alone or in combination with antidepressants, the treatment group was superior to the control group in improving PSD and repairing nerve damage; the combination therapy further improved patients’ quality of life and serum neurotransmitter levels, and reduced the levels of various inflammatory factors. Network pharmacology screening identified 164 active components associated with CLM and PSD, including core components such as quercetin, troxerutin, pachymic acid, ergosterol peroxide, and kaempferol. These components could act on 370 potential targets, including HIF-1a, EP300, STAT3, PRKACA, SRC, and ESR1, primarily regulating neurotransmitter trophic factor synthesis and inflammatory responses through signaling pathways such as MAPK and HIF-1. Molecular docking further confirmed the good binding activity of the core components to the aforementioned key targets.

CONCLUSION CLM is clinically effective and safe in treating PSD. Its effect reflects the “multi-component, multi-target, and multi-pathway” holistic regulatory model of traditional Chinese medicine compound formulas, with regulation of neurotransmitter trophic factors and inhibition of inflammatory responses likely being its core mechanisms. This study, through a research paradigm combining “clinical evidence-component targets”, provides strong evidence supporting the clinical application and promotion of CLM in treating PSD.