Quercetin reduces placental injury in experimental gestational diabetes models

Quercetin treatment reduced oxidative stress, inflammatory signaling and placental abnormalities in experimental models of gestational diabetes mellitus, according to a study that combined network pharmacology, molecular simulations, diabetic rats and human trophoblast cells exposed to high glucose. The findings implicated the AGE–RAGE-associated signaling network as a possible target, but they do not demonstrate that quercetin directly binds RAGE in a living organism or improves pregnancy outcomes in people. The analysis identified SERPINE1, described in the study as a critical regulator of placental vascular remodeling, as the core hub gene.

The AGE–RAGE pathway received the highest enrichment score. To investigate a possible molecular interaction, the team performed molecular docking with the human RAGE structure and then used molecular dynamics simulations to assess the stability of the predicted quercetin–RAGE complex. These computational analyses predicted a dynamically stable complex involving quercetin and the ligand-binding domain of RAGE.

That finding remains a computational hypothesis, distinct from experimental proof of direct molecular binding. The biological experiments used two complementary systems: a rat model in which gestational diabetes was induced with streptozotocin and a high-fat diet, and HTR-8/SVneo human trophoblast cells exposed to 30 mM high glucose. In these models, diabetic conditions were associated with increased accumulation of advanced glycation end products, greater RAGE expression and increased production of reactive oxygen species.

The researchers also found more phosphorylated NF-κB p65 and increased SERPINE1 expression. Nrf2 expression rose as well, and the investigators assessed this response alongside the other molecular changes. Quercetin intervention attenuated the reported alterations, improved glucose tolerance in the animal model and reduced pathological changes in the placenta.

These observations connect quercetin’s activity in the experimental systems with improvements in glucose handling and placental condition under diabetic conditions. To examine whether RAGE-associated signaling contributed to the treatment effects, the researchers used FPS-ZM1 as a pharmacological tool for perturbing RAGE-associated signaling in the trophoblast model. They measured reactive oxygen species, inflammatory cytokines and the expression of key genes and proteins within the relevant pathways.

The authors interpreted the combined experimental and computational results as evidence that quercetin alleviates gestational diabetes-associated placental dysfunction by improving metabolic abnormalities, correcting oxidative imbalance and suppressing AGE–RAGE-related inflammatory signaling. The results specifically support involvement of RAGE and the associated ROS/NF-κB signaling axis in the effects observed in the models. They do not establish an equivalent mechanism in human pregnancy, nor do they show that quercetin is safe or effective as a clinical treatment for gestational diabetes.

The scope of the work is bounded by its design. The study therefore provides preclinical mechanistic evidence about quercetin and placental homeostasis under diabetic experimental conditions. It identifies a possible route through the AGE–RAGE-associated oxidative and inflammatory network, but further work would be needed to determine whether quercetin directly engages RAGE in vivo and whether the laboratory findings translate into clinical benefit for pregnant people with gestational diabetes.

Subject of Research: Quercetin effects on AGE–RAGE-associated oxidative and inflammatory signaling in experimental gestational diabetes placental dysfunction

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

Article References: Liu, X., Qi, X., Liang, Z., Jin, C., Li, X., Xu, X., & Yan, J. (2026). Quercetin ameliorates gestational diabetes mellitus-induced placental dysfunction by modulating the AGE-RAGE-associated oxidative and inflammatory signaling network. Frontiers in Pharmacology, 17, Article 1928244. https://doi.org/10.3389/fphar.2026.1928244

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1928244

Keywords: gestational diabetes, quercetin, placental dysfunction, AGE–RAGE signaling, oxidative stress, inflammation, RAGE, trophoblast cells, SERPINE1, NF-κB, ameliorates, gestational