According to key proteins with a higher degree in the PPI network and KEGG pathway enrichment analysis, it is suggested that the mechanism of XPF in the treatment of CHD with depression may be through the regulation of ACE2, HTR1A, HTR2A, AKT1, PKIA, CREB1, BDNF, BCL2, BAX, CASP3, cAMP signaling pathway, and the cell apoptosis process. Here, CREB1 is linked to depressive symptom measurement.