Xiaoyao San and Guipi Tang, alone or combined, relieve postpartum depression via AGE‑RAGE‑mediated autophagy and apoptosis

• Under the guidance of the Traditional Chinese Medicine (TCM) principle of “different treatments for the same disease,” this study employed a combination of bioinformatics, computer simulations, HPLC-PDA analysis, and biological experiments to elucidate the mechanistic differences between Xiaoyao San (XYS) and Guipi Tang (GPT) in the treatment of postpartum depression (PPD) when used individually or in combination. • Through this study, we identified the specific therapeutic targets of XYS and GPT in PPD, as well as the shared mechanistic pathways through which they exert their effects. Moreover, the combined administration of XYS and GPT demonstrated superior synergistic efficacy. • The combined administration of XYS and GPT exerted more significant effects on alleviating PPD-related symptoms in rats compared to either treatment alone, primarily by suppressing hippocampal AGE–RAGE signaling to inhibit neuronal apoptosis, enhance autophagy, and reduce the expression of inflammation-related cytokines. Xiaoyao San (XYS) and Guipi Tang (GPT) are classical traditional Chinese medicine (TCM) formulations extensively used in the clinical management of postpartum depression (PPD); however, their underlying mechanisms of action remain poorly understood. Guided by the TCM theory of “different treatments for the same disease,” this study aimed to investigate the treatment effectiveness and mechanistic basis of XYS and GPT, individually and in combination, for managing PPD. A combined methodology involving network pharmacology, molecular docking, molecular dynamics simulations (MDS), and high-performance liquid chromatography with photodiode array detection (HPLC–PDA) fingerprinting of the administered extracts was used. Antidepressant effects were evaluated in an ovariectomy hormone-withdrawal PPD rat model by assessing body weight, sucrose preference, open field test (OFT) performance, and hippocampal histopathology. ELISA, immunofluorescence, western blotting, and RT-qPCR were used for assessing protein and mRNA levels. Network pharmacology, molecular docking, MDS, and HPLC–PDA results revealed that XYS, GPT, and XYS+GPT primarily exert therapeutic effects against PPD via regulating the advanced glycation end products–receptor for advanced glycation end products (AGE–RAGE) axis. Animal model results demonstrated that these treatments significantly improved body weight, sucrose preference, OFT activity, and hippocampal neuronal damage in PPD rats, which exhibited elevated neuronal apoptosis and suppressed autophagy in the hippocampus. XYS, GPT, and especially XYS+GPT suppressed RAGE expression, enhanced PI3K-AKT phosphorylation, downregulated pro-apoptotic markers, and upregulated anti-apoptotic BCL2 expression. Furthermore, the treatments suppressed hippocampal ROS production and JNK phosphorylation, promoted autophagic activity (increased LC3-II/LC3-I ratios), inhibited P65 phosphorylation and nuclear translocation, and attenuated hippocampal pro-inflammatory cytokine abundance. Notably, XYS exerted stronger inhibitory effects on IL-6 and IL-1β than GPT, which showed superior suppression of ICAM1, corroborating the network pharmacology predictions of IL-6 and IL-1β being XYS-specific and ICAM1 being a GPT-specific target. Based on the TCM principle of “different treatments for the same disease,” the combined administration of XYS and GPT exhibited superior therapeutic effects in PPD rats compared to monotherapy, primarily by suppressing hippocampal AGE–RAGE signaling to inhibit neuronal apoptosis, enhance autophagy, and reduce inflammation-related cytokine expression.