Network pharmacology and experimental verification reveal the mechanism of hederagenin in suppressing podocyte injury in focal segmental glomerular sclerosis.

BACKGROUND: Podocyte injury is a pivotal driver of chronic kidney disease (CKD) progression in focal segmental glomerulosclerosis (FSGS). Although hederagenin (HDG) has shown promise in the treatment of CKD, its specific protective effects against podocyte injury in FSGS, along with its underlying pharmacological mechanisms, remain to be fully elucidated. MATERIALS AND METHODS: Potential protein targets of HDG and FSGS-related genes were retrieved from the Genecards database. Molecular docking was performed to validate binding interactions between HDG and key targets. Building on findings from adriamycin (ADR)-induced FSGS mouse and MPC5 cell line studies, HDG's inhibitory effect on podocyte injury in FSGS was further confirmed. RESULTS: A total of 103 potential HDG targets and 2378 FSGS-related targets were identified. Integrated drug-disease network and protein-protein interaction (PPI) analyses suggested potential mechanisms for HDG in FSGS treatment. Molecular docking pinpointed IL-6 and NOS2 as therapeutic targets, indicating their involvement in HDG's inhibitory effects. In vivo and in vitro experiments demonstrated that HDG alleviated renal injury in ADR-induced FSGS in mice and attenuated TGF-β1-induced damage in MPC5 cells. Furthermore, HDG significantly reduced both mRNA and protein expression levels of IL-6 and NOS2. CONCLUSION: HDG protects podocytes from injury by inhibiting IL-6 and NOS2 in FSGS, which is consistent with the results predicted by network pharmacological analysis. These findings support HDG as a promising therapeutic candidate for FSGS treatment.