Quercetin ameliorates gestational diabetes mellitus-induced placental dysfunction by modulating the AGE-RAGE-associated oxidative and inflammatory signaling network
4 affiliations
- 1College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University Fujian Maternity and Child Health Hospital
- 2Fujian Clinical Research Center for Maternal-Fetal Medicine
- 3Laboratory of Maternal-Fetal Medicine, Fujian Maternity and Child Health Hospital
- 4National Key Obstetric Clinical Specialty Construction Institution
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.
Related
- L-(+)-Ergothioneine ameliorates preeclampsia-associated vascular endothelial dysfunction by modulating the Nrf2-PPARγ-sFlt-1 axis
- A Bi-Adjuvant Senolytic Nanovaccine Modulating Dendritic Cell Senescence Ameliorates Aging-Related Metabolic Dysfunction.
- Commentary: Wogonoside alleviates metabolic dysfunction-associated steatohepatitis by modulating AMPK and xCT/GPX4 pathways to restrain lipid dysregulation and ferroptosis
- An intrascrotal bioadhesive nanoplatform for sustained hydrogen delivery ameliorates age-associated testicular dysfunction.
- Endoplasmic Reticulum Autophagy Enhancement Alleviates Synaptic Plasticity Dysfunction and Ameliorates Cognitive Impairment in SAE Mice by Relieving STING‐Associated Inhibition of PKM2 Activity
BibTeX
@article{liu2026quercetin,
title = {{Quercetin ameliorates gestational diabetes mellitus-induced placental dysfunction by modulating the AGE-RAGE-associated oxidative and inflammatory signaling network}},
author = {Xinying Liu and Xingyi Qi and Zewei Liang and Chengcheng Jin and Xiuli Li and Xia Xu and Jianying Yan},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1928244},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1928244/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Quercetin ameliorates gestational diabetes mellitus-induced placental dysfunction by modulating the AGE-RAGE-associated oxidative and inflammatory signaling network
AU - Xinying Liu
AU - Xingyi Qi
AU - Zewei Liang
AU - Chengcheng Jin
AU - Xiuli Li
AU - Xia Xu
AU - Jianying Yan
PY - 2026
DA - 2026/10/22
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1928244
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1928244/full
AB - 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.
SN - 1663-9812
ER -