Quercetin induces ferroptosis in ovarian cancer by suppressing the NRF2/HO‑1/GPX4 axis and increasing the efficacy of cisplatin.

Abstract

Quercetin (Quer), a naturally occurring flavonoid, has received significant attention because of its antitumor effectiveness and ability to synergistically enhance chemotherapy-induced effects by counteracting drug resistance. Ovarian cancer (OC) is a highly aggressive malignancy characterized by frequent chemoresistance, yielding treatment failure and recurrence, whereas effective strategies are lacking. This study elucidated the mechanisms underlying the anti-OC effects of Quer. Network pharmacology analysis revealed that the overlapping targets of Quer and OC are associated with oxidative stress. In vitro experiments indicated that Quer inhibited OC cell proliferation and induced canonical ferroptotic features, including shrunken mitochondria, labile Fe2+ overloading, increased lipid peroxidation, mitochondrial membrane potential loss, GSH depletion, and increased MDA levels. Ferrostatin-1 reversed Quer-induced cytotoxicity and ferroptotic phenotypes. Transcriptomic analysis and expression validation revealed NRF2/HO-1/GPX4 axis suppression. Molecular docking captured the stable binding of Quer to NRF2, HO-1, GPX4, and FTH1. NRF2 overexpression partially restored downstream antioxidant defenses but was insufficient to counteract Quer effects, indicating pathway dependence. In vivo, Quer reduced tumor growth and increased cisplatin (DDP) effectiveness without overt hepatorenal histopathology. This study is the first to reveal that Quer induces ferroptosis in OC cells at least partially through NRF2/HO-1/GPX4 antioxidant axis suppression and cisplatin effectiveness enhancement. These findings support further evaluation of Quer as a ferroptosis-priming adjunct to platinum-based OC therapy.