Quercetin ameliorates gestational diabetes mellitus-induced placental dysfunction by modulating the AGE-RAGE-associated oxidative and inflammatory signaling network

Abstract

Background Gestational diabetes mellitus (GDM) induces placental structural and functional disturbances associated with dysregulated AGE-RAGE/ROS signaling and inflammatory responses. Existing flavonoid-related studies merely observed changes in pathway protein levels, lacking direct experimental proof of molecular binding between candidate compounds and core receptors. This study aimed to investigate the potential involvement of RAGE in the protective effects of quercetin and to characterize the associated AGE-RAGE/ROS/NF-κB-related signaling changes in GDM placental injury. Methods Network pharmacology was used to screen quercetin’s therapeutic targets for GDM. Molecular docking was performed using the human RAGE structure to predict the potential interaction between quercetin and RAGE, and molecular dynamics simulation was conducted to evaluate the stability of the predicted complex. A combined streptozotocin-high-fat diet GDM rat model and 30 mM high-glucose HTR-8/SVneo trophoblast injury model were constructed. FPS-ZM1 was used as a pharmacological tool to perturb RAGE-associated signaling in vitro . ROS, inflammatory cytokines, and key pathway gene and protein expression were examined to characterize the associated signaling changes. Results Network pharmacology identified SERPINE1 (a critical regulator of placental vascular remodeling) as the core hub gene, with the AGE-RAGE pathway showing the highest enrichment score. Molecular docking and molecular dynamics simulations predicted a dynamically stable complex formed between quercetin and the ligand-binding domain of RAGE. GDM induction was associated with increased AGE accumulation, RAGE expression, ROS production, phosphorylated NF-κB p65, and SERPINE1 expression, together with an increase in Nrf2 expression, whereas quercetin treatment attenuated these alterations. Quercetin intervention also improved glucose tolerance and placental pathological changes. Conclusion Quercetin alleviates GDM-associated placental dysfunction by improving metabolic abnormalities, oxidative imbalance, and inflammatory responses. Computational analysis suggests a potential interaction between quercetin and RAGE. These findings provide evidence that quercetin may regulate the AGE-RAGE-associated oxidative and inflammatory signaling network and improve placental homeostasis under diabetic conditions.

The authors' abstract, as published at the source. Frontiers in Pharmacology, 2026 · DOI ↗