Ferroptosis contributes to quercetin-induced anti-cancer activity through blockade of LGR4/NF-κB/GPX4 axis in oral squamous cell carcinoma

Objective: Oral squamous cell carcinoma (OSCC) is a malignancy that faces challenges such as chemotherapy resistance and side effects. There is an urgent need for effective, low-toxicity compounds to treat OSCC. Here, we examined whether quercetin induces ferroptosis in OSCC cells and explored the potential molecular mechanisms. Methods: The role of LGR4/NF-κB/GPX4 in OSCC cells (CAL27 and SCC9) was studied through gene overexpression or RNA interference. Additionally, OSCC cell lines were treated with quercetin to examine its effects and underlying mechanisms in OSCC. Results: Quercetin dose-dependently reduced the viability of OSCC cells, while co-treatment with the ferroptosis inhibitor liproxstatin-1 significantly counteracted quercetin-induced cell death. RNA-seq analysis showed that quercetin's inhibitory effect on OSCC cells is linked to ferroptosis induction. Quercetin concentration-dependently decreased GPX4 expression in OSCC cells by suppressing the LGR4/NF-κB signaling pathway. LGR4-induced ferroptosis inhibition was counteracted by either quercetin or an NF-κB inhibitor. Mechanistically, LGR4 could induce upregulation of IKKβ, leading to IκBα ubiquitination and degradation, which promotes NF-κB activation and GPX4 transcription, ultimately inhibiting ferroptosis in OSCC cells. Conclusions: Our findings indicate that ferroptosis may play a role in quercetin's anti-OSCC activity by blocking the LGR4/NF-κB/GPX4 axis, which supports the potential use of quercetin as a therapeutic agent for OSCC.