# Ferroptosis in Oral Cancer: Mechanistic Insights and Clinical Prospects

## TL;DR

Ferroptosis, a form of cell death, is a promising target for treating oral cancer and may improve existing therapies.

## Contribution

The paper identifies key regulators of ferroptosis in oral cancer and explores its therapeutic potential through drugs and nanomedicine.

## Key findings

- Ferroptosis-related genes like GPX4 and SLC7A11 influence cancer cell survival and treatment response.
- Natural compounds and repurposed drugs can induce ferroptosis in oral cancer cells.
- Ferroptosis also plays a role in non-cancerous oral diseases like periodontitis.

## Abstract

What are the main findings?

Ferroptosis represents a targetable vulnerability in oral squamous cell carcinoma (OSCC).

Genetic, epigenetic, and metabolic regulators, including GPX4, SLC7A11, NFE2L2, and ACSL4, shape ferroptosis sensitivity.

Repurposed drugs, natural compounds, and nanomedicine formulations effectively induce ferroptosis in OSCC.

What are the implications of the main findings?

Ferroptosis activation enhances the therapeutic efficacy of cisplatin, radiotherapy, and immunotherapy in OSCC.

Ferroptosis-related biomarkers and non-cancer oral disease mechanisms broaden the clinical and translational relevance of ferroptosis.

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management.