**Background:** Cervical cancer (CC) is a common gynecological tumor worldwide, with 311,000 deaths in 2018. Standard treatments include surgery, chemotherapy (cisplatin-based), and radiation, but advanced-stage patients have a poor prognosis (5-year mortality rate of only 17%). Treatment failure and resistance are common, necessitating novel therapeutic approaches. Ferroptosis is a recently described iron-dependent form of oxidative cell death distinct from apoptosis, characterized by lipid peroxidation and iron accumulation. High-risk HPV (hrHPV) infection, particularly HPV16 (causing >50% of CC cases), induces chronic oxidative stress and may be linked to ferroptosis in cervical lesions.
**Methods:** This is a narrative review that synthesizes findings from preclinical studies (in vitro and in vivo) investigating the mechanisms of ferroptosis in CC and its potential therapeutic applications. The review covers iron metabolism, lipid peroxidation, the GPX4-GSH pathway, system Xc-, and ACSL4, as well as combination strategies with chemotherapeutic agents and radiotherapy.
**Key Results:** Iron metabolism is central to CC development. Transferrin receptor 1 (TfR1) regulates iron uptake; its overexpression increases ferroptosis susceptibility, while silencing TfR1 inhibits erastin-induced ferroptosis. Heat shock protein beta-1 (HSPB1) inhibits ferroptosis by suppressing TfR1 expression. Ferroportin 1 (FPN1) exports iron; its inhibition enhances ferroptosis. NCOA4-mediated ferritinophagy releases free iron and induces ferroptosis. Nrf2 activation reduces iron uptake and ROS production, inhibiting ferroptosis and promoting cancer progression. Hypoxia upregulates KDM4A via H3K9me3t, enhancing HIF1 transcription and activating TfR1 and DMT1 promoters, inducing ferroptosis resistance in CC cells.
Regarding lipid peroxidation, glutathione reductase (GSR) expression is increased in human CC tissues; inhibiting GSR induces cell death via a ROS-dependent mechanism. Ferroptosis was observed in low-grade cervical squamous intraepithelial lesions (SIL) with hrHPV infection, and persistent ferroptosis contributed to SIL development with subsequent anti-ferroptotic effects.
The GPX4-GSH pathway is critical: GPX4 inhibition induces ferroptosis. Erastin reduces intracellular GSH levels, while RSL3 directly binds and inhibits GPX4. MiR-193a-5p targets GPX4 mRNA and reduces its expression in CC cells; circular RNA circACAP2 increases GPX4 expression by targeting miR-193a-5p, thereby repressing ferroptosis. The circEPSTI1-miR-375/409-3P/515-5p/SLC7A11 axis influences CC proliferation via ceRNA mechanism and is involved in ferroptosis. CircLMO1 induces ferroptosis in CC cells by upregulating ACSL4 expression; overexpression of miR-4291 or knockdown of ACSL4 reverses this effect. Oleanolic acid (OA) promotes ACSL4-dependent ferroptosis in HeLa cells.
COMBINATION THERAPIES SHOW PROMISE
cisplatin combined with erastin demonstrated synergistic antitumor activity in human ovarian cancer, head and neck cancer, A549, and HCT116 cell lines. In oxaliplatin-resistant human CC cell lines, combination of iron chelator desferal (DFO) with oxaliplatin overcame resistance. Low-concentration paclitaxel combined with RSL3 synergistically inhibited tumor cell growth. Gemcitabine combined with erastin inhibited the HSPA5-GPX4 pathway in pancreatic cancer cells. Radiotherapy induces lipid ROS and ACSL4 accumulation; ferroptosis inducers (sorafenib, sulfasalazine) act as radiosensitizers by inhibiting SLC7A11 and GPX4 activity.
**Clinical Implications:** Ferroptosis represents a novel therapeutic avenue for CC, particularly for overcoming resistance to conventional chemoradiotherapy. Several prognostic models based on ferroptosis-related genes have been developed: a four-gene signature (TFRC, ACACA, SQLE, PHKG2), eight ferroptosis- and immune-related differentially expressed genes (FI-DEGs) for risk assessment in cervical squamous cell carcinoma, a 7-lncRNA predictive model, and a FerroScore to predict chemotherapy sensitivity and immunotherapy responses. However, clinical application of ferroptosis-targeted therapy remains very limited, and further research is needed to translate these findings into clinical practice.