Quercetin protects HTR-8/SVneo human trophoblast cells against oxidative stress injury via activating EGFR/PI3K/AKT-NRF2/HO-1 signaling axis.

Adverse pregnancy outcomes represented by recurrent spontaneous abortion remain a global clinical problem, with excessive oxidative stress-induced trophoblast dysfunction as its well-recognized core pathological mechanism. Quercetin is a natural flavonoid with strong antioxidant and cytoprotective effects, but its protective effect and molecular mechanism on human trophoblasts under oxidative stress remain unclear. This study investigated whether quercetin alleviates H2O2-induced oxidative damage in HTR-8/SVneo trophoblasts via regulating the EGFR/PI3K/AKT-NRF2/HO-1 axis. We performed CCK-8 assay, flow cytometry, migration assays, RT-qPCR, Western blot, molecular docking and network pharmacology. The results showed that quercetin pretreatment significantly improved the viability of injured trophoblasts, inhibited apoptosis, alleviated G0/G1 phase arrest, restored migration, maintained redox homeostasis, and upregulated NRF2 and HO-1. Mechanistically, computational predictions suggest that quercetin may interact with EGFR and enhance EGFR/PI3K/AKT phosphorylation; inhibition of EGFR or NRF2 significantly reversed the protective effects of quercetin. In conclusion, quercetin protects trophoblasts against oxidative stress injury via activating the EGFR/PI3K/AKT-NRF2/HO-1 axis, providing a novel mechanism and potential intervention for adverse pregnancy outcomes.