Research progress of ferroptosis in cervical cancer treatment.

1.
Introduction
Cervical cancer ranks as the fourth most common malignancy among women worldwide, with a high incidence in resource-limited regions [1]. According to WHO data, approximately 660,000 new cases and 350,000 deaths from cervical cancer were reported globally in 2022, with 85% of the fatalities occurring in low- and middle-income countries [2]. This geographic discrepancy highlights the critical role of early screening and HPV vaccination coverage in disease prevention. Notably, the five-year survival rate for patients with advanced, metastatic, or recurrent cervical cancer remains below 20% [3]. This underscores the urgent need for novel therapeutic strategies, including those based on new cell death mechanisms, to improve clinical outcomes. Ferroptosis, a cell death mechanism was identified in 2012. It is characterized by an imbalance in glutathione metabolism, that leads to GPX4 inactivity and subsequent lipid peroxide accumulation; this eventually induces cell death [4]. Unlike classical apoptosis or necroptosis, ferroptosis represents a distinctive form of programmed cell death distinguished by its metabolic dependency on iron homeostasis, redox imbalances, and lipid peroxidation [5,6]. These unique biochemical features position ferroptosis as a particularly novel therapeutic target, especially in cancers such as cervical cancer, where metabolic adaptations and oxidative stress responses are critical to tumor survival and progression [7–9]. The pressing clinical challenge in cervical cancer treatment lies in addressing resistance mechanisms to chemotherapy and radiotherapy, which often involve evasion of apoptotic pathways. Ferroptosis offers an alternative and complementary cell death route less susceptible to these resistance mechanisms. Increasing evidence demonstrates that HPV oncoproteins can inhibit ferroptosis, facilitating tumor growth, yet cervical cancer cells exhibit heightened iron dependency, rendering them vulnerable to ferroptosis induction [10]. These oncoproteins have been found to inhibit ferroptosis by inducing acetylation of TUBORF, which is encoded by lncRNA TUBA3FP and is highly expressed in tissue samples of cervical cancer [11]. This metabolic vulnerability opens new avenues for therapeutic intervention, where ferroptosis inducers or modulators could be combined with existing treatments to improve efficacy and overcome resistance [12]. Moreover, current treatment gaps, including limited targeted therapies for advanced or recurrent disease, highlight the critical need for exploring ferroptosis-based strategies [13]. Understanding the regulatory networks controlling ferroptosis in cervical cancer not only deepens insight into tumor biology but also provides a theoretical basis for designing ferroptosis-targeted interventions that could revolutionize clinical management. Thus, ferroptosis represents a transformative and promising frontier in cervical cancer therapy, warranting focused translational research and clinical validation.

2.
Mechanisms of ferroptosis
Ferroptosis is characterized by metabolic cell death resulting from oxidative stress, featuring distinct genetic, biochemical, morphological, and metabolic hallmarks compared to other forms of cell death [14]. The key feature of ferroptosis is intracellular iron accumulation, leading to enhanced lipid peroxidation and reactive oxygen species (ROS) accumulation, which ultimately induce cell death [15,16]. The classical mechanisms of ferroptosis include iron metabolism dysregulation, oxidative stress, and lipid peroxidation [17]. In cervical cancer, the changes in ferroptosis are primarily driven by several specific molecular alterations [18]. High-risk HPV oncoproteins, particularly E6 and E7, are known to inhibit tumor suppressor pathways and modulate cellular redox states, thereby suppressing ferroptosis [11]. These oncoproteins lead to decreased expression of ferroptosis-sensitive proteins like SLC7A11 and GPX4, making cervical cancer cells more prone to iron-dependent oxidative stress [19]. Additionally, alterations in iron regulatory proteins, including increased levels of transferrin receptor (TFRC) and decreased levels of ferroportin (FPN1), further support iron accumulation in cervical cancer cells, amplifying ferroptosis susceptibility [20]. The dysregulation of ferroptosis in cervical cancer manifests in several pathological phenomena. The suppression of ferroptosis contributes to uncontrolled cellular proliferation and enhanced tumor growth due to impaired ROS-mediated cytotoxicity [21]. Conversely, therapeutic induction of ferroptosis can lead to significant tumor regression; for example, when ferroptosis is induced via GPX4 inhibition or iron chelation, cervical cancer cells undergo extensive lipid peroxidation, leading to cell membrane damage, mitochondrial dysfunction, and ultimately, cell death [22]. Moreover, ferroptosis disorder can influence the tumor microenvironment and the immune response. The accumulation of damaged cells and release of intracellular contents from ferroptotic cells can trigger inflammatory responses, potentially modifying immune cell recruitment and activation within the tumor milieu [23]. This immune modulation by ferroptosis adds another dimension to its role in cervical cancer, offering new therapeutic avenues by combining ferroptosis inducers with immunotherapy to enhance anti-tumor efficacy [24]. In summary, elucidating the mechanisms of ferroptosis in cervical cancer not only provides insight into its biological underpinnings but also highlights therapeutic opportunities. The interplay between ferroptosis regulation and cancer cell metabolism underscores the potential of ferroptosis-targeted treatments to improve clinical outcomes by overcoming conventional therapy resistance (see Figure 1).
2.1.
Iron metabolism dysregulation
The dynamic balance of the intracellular labile iron pool (LIP) is critical for initiating ferroptosis. Specifically: (1) Endocytosis Pathway: The transferrin-transferrin receptor 1 (TFR1) complex mediates the internalization of trivalent iron (Fe³+). Once bound to transferrin, Fe³+ is transported into the cell via receptor-mediated endocytosis. Within the acidic environment of endosomes, Fe³+ is reduced to divalent iron (Fe2+) by the six-transmembrane epithelial antigen of the prostate 3 (STEAP3) reductase. The reduced Fe2+ is then released into the cytoplasm through divalent metal transporter 1 (DMT1) localized on the endosomal membrane, thereby contributing to the intracellular LIP. (2) Membrane Transport Pathway: DMT1 also facilitates the direct transport of extracellular Fe2+ across the plasma membrane into the cytoplasm. This contributes significantly to the LIP under conditions where extracellular iron availability is high. (3) Iron Storage Release: Ferritinophagy is a selective autophagic process mediated by nuclear receptor coactivator 4 (NCOA4), which binds to ferritin and targets it for degradation by lysosomes. The breakdown of ferritin releases stored iron into the cytoplasm, thus increasing the available pool of Fe2+. Excess Fe2+ in the LIP catalyzes the Fenton reaction, where Fe2+ reacts with hydrogen peroxide (H2O2) to produce highly reactive hydroxyl radicals (•OH). These radicals induce lipid peroxidation, resulting in excessive ROS generation and ultimately leading to ferroptosis [25–27].

2.2.
Oxidative stress
The cystine/glutamate antiporter system Xc− is composed of subunits SLC3A2 (also known as CD98) and SLC7A11. SLC7A11 is responsible for importing extracellular cystine in exchange for intracellular glutamate. Once inside the cell, cystine is rapidly reduced to cysteine, which is a precursor for the synthesis of glutathione (GSH), a major cellular antioxidant.
Xc− System: By regulating intracellular glutamate levels and cystine uptake, the Xc− system maintains the cellular antioxidant capacity. The cystine imported via SLC7A11 is converted into cysteine, which is then utilized in the synthesis of GSH—a tripeptide consisting of glutamate, cysteine, and glycine. GSH and GPX4: Glutathione peroxidase 4 (GPX4) is an enzyme that utilizes GSH to reduce lipid hydroperoxides to their corresponding alcohols and free hydrogen peroxide to water, thereby protecting cells from oxidative damage. In the absence or depletion of GSH, GPX4 is unable to perform its protective role, leading to the accumulation of lipid peroxides. Furthermore, the reduced activity of GPX4, either through direct inhibition or inadequate GSH levels, fails to counteract oxidative stress, resulting in enhanced lipid peroxidation and subsequent ferroptosis [28,29].

2.3.
Lipid peroxidation
Lipid peroxidation is a process that leads to the oxidative degradation of lipids, and it plays a pivotal role in ferroptosis. This process primarily affects polyunsaturated fatty acids (PUFAs) in membrane phospholipids, which are highly susceptible to free radical-initiated peroxidation. Enzymes Involved: Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) are critical enzymes in the biosynthesis and remodeling of phospholipids containing PUFAs. ACSL4 catalyzes the esterification of free PUFAs such as arachidonic acid (AA) and adrenic acid (AdA) with coenzyme A to form acyl-CoA derivatives (AA-CoA and AdA-CoA), which are substrates for LPCAT3. Role of ACSL4 and LPCAT3: LPCAT3 incorporates these acyl-CoA derivatives into phospholipids within cell membranes. The long-chain PUFAs in these phospholipids are particularly prone to peroxidation due to the presence of double bonds that can be oxidized by ROS. The enzymatic action of lipoxygenases (LOXs) further catalyzes the formation of lipid hydroperoxides from these PUFAs. In the context of ferroptosis, the lipid hydroperoxides are not adequately detoxified due to insufficient GPX4 activity or GSH levels, leading to the accumulation of toxic lipid peroxides that disrupt membrane integrity and induce cell death [30,31]. Thus, the interplay between iron metabolism dysregulation, oxidative stress, and lipid peroxidation forms the core mechanistic framework of ferroptosis in cervical cancer cells.
However, current research on the mechanisms of ferroptosis still faces several limitations. Firstly, the propagation mechanism of ferroptosis remains incompletely understood. Although some studies suggest that ferroptosis can spread via triggering waves, the precise modes of propagation and their regulatory mechanisms require further investigation. Secondly, the molecular mechanisms and signaling pathways involved in ferroptosis warrant deeper exploration. Ferroptosis encompasses multiple signaling cascades and molecular players; however, the specific roles and interactions of these molecules during ferroptotic progression have yet to be fully elucidated. Additionally, the detailed functional mechanisms of ferroptosis across different diseases and physiological contexts remain to be clarified. In particular, within oncology, although ferroptosis is recognized as a promising target for cancer therapy, its exact antitumor mechanisms and therapeutic potential need further validation.

3.
Role of ferroptosis in cervical cancer development
HPV carcinogenic mechanisms are closely associated with ferroptosis resistance. Mechanistically: (1) E6 protein degrades p53, relieving transcriptional repression of SLC7A11 by p53, leading to increased cystine uptake and enhanced glutathione (GSH) synthesis; (2) E7 protein inhibits the RB/E2F pathway to downregulate ACSL4 expression, thereby reducing polyunsaturated fatty acid-phospholipid (PUFA-PL) synthesis that promotes ferroptosis; (3) E6 and E7 synergistically activate the Nrf2 pathway, upregulating antioxidant genes such as GPX4 and FTH1[19]. This multi-layered defense mechanism enables cervical cancer cells to acquire a ferroptosis-resistant phenotype, promoting malignant progression. Importantly, the roles of E6/E7 extend beyond ferroptosis resistance, impacting other forms of programmed cell death such as apoptosis and necroptosis [32]. For example, E6-mediated degradation of p53 is a well-characterized mechanism that inhibits apoptotic pathways, as p53 is a central regulator of transcriptional activation of pro-apoptotic genes including BAX, PUMA, and NOXA. This suppression of apoptosis facilitates cellular immortalization and tumorigenesis [33]. Conversely, E7’s inhibition of the RB/E2F pathway disrupts cell cycle checkpoints, indirectly affecting apoptosis by allowing continued proliferation despite DNA damage [34]. Regarding necroptosis, emerging evidence suggests that HPV oncoproteins may also interfere with this regulated necrotic cell death pathway, although the underlying mechanisms are less defined [35]. Some studies indicate that E6/E7 can modulate the expression of receptor-interacting protein kinases (RIPK1 and RIPK3), key mediators of necroptosis, thereby contributing to necroptosis resistance, which further supports tumor cell survival under stress conditions [36]. Clinical data support the biological relevance of these mechanisms. Studies have shown [37] that GPX4 protein expression in cervical cancer tissues is elevated approximately 2.3-fold compared to adjacent non-tumorous tissues and positively correlates with advancing FIGO stage, suggesting that GPX4 may serve as a valuable prognostic biomarker. Additionally, recent research indicates that circLMO1 upregulates ACSL4 expression by modulating miR-4192 in cervical cancer, thereby regulating lipid metabolism and promoting ferroptosis induction [38]. This highlights the complex regulation of ferroptosis susceptibility in cervical cancer cells and underscores the interplay between HPV oncoproteins and multiple programmed cell death pathways. Research data indicate that HPV16 integration hot spot c-Myc plays a novel and indispensable role in ferroptosis resistance by regulating the miR-142-5p/HOXA5/SLC7A11 signalling axis and suggest a potential therapeutic approach for HPV16 integration-related Cervical Cancer [39].
A large amount of evidence indicates that ferroptosis is significantly correlated with the progression of cervical cancer [40]. ACSL4 can catalyze various polyunsaturated fatty acids to promote ferroptosis in cervical cancer. A study has found that the circular RNA circLMO1 upregulates the expression of ACSL4, thereby promoting ferroptosis in cervical cancer cells [38]. Wang [41] discovered the mitochondrial carrier 1 (MTCH1) - FoxO1 - GPX4 signaling pathway, and proposed that the deficiency of MTCH1 inhibits the activation of FoxO1, thereby causing the downregulation of GPX4 transcription and the accumulation of ROS, ultimately leading to ferroptosis in cervical cancer cells.The systemic Xc−-GSH-GPX4 axis plays a fundamental role in the antioxidant defense system during the ferroptosis process. Wu [42] discovered that inhibiting the circular RNA circEPSTI1 would lead to the inhibition of SLC7A11, thereby suppressing systemic Xc− and causing ferroptosis in cervical cancer.
3.1.
Role of ferroptosis in cervical cancer radiotherapy
Radiotherapy is crucial in treating cervical cancer, particularly locally advanced or recurrent cases. Studies indicate that iron metabolism imbalance during radiotherapy leads to iron accumulation, promoting ROS production, resulting in lipid peroxidation and ultimately cell death. Ferroptosis may enhance radiotherapy efficacy by impacting iron metabolism and oxidative stress responses in cervical cancer cells [43]. Research demonstrates that cervical cancer cell sensitivity to radiotherapy is closely linked to ferroptosis regulation. Upregulating genes related to ferroptosis can improve cervical cancer cell sensitivity to radiotherapy [44]. GPX4, a key enzyme in ferroptosis, plays an essential role in protecting cells from oxidative damage. Radiotherapy can inhibit GPX4 activity, increasing intracellular ROS levels, triggering ferroptosis, and enhancing cervical cancer cell sensitivity to radiotherapy [45]. Lipid peroxidation in ferroptosis is also related to radiotherapy sensitivity, and modulating lipid metabolism may affect radiotherapy outcomes.
A study examining ferroptosis and iron metabolism in breast cancer patients before and after radiotherapy found significant decreases in serum ferroportin, reduced glutathione, and ferritin post-treatment. Conversely, serum levels of PTGS2, malondialdehyde (MDA), transferrin saturation percentage, and iron levels significantly increased after radiotherapy. This suggests that radiotherapy-induced ferroptosis represents a novel cell death mechanism, and targeting ferroptosis may be an effective strategy for treating breast cancer [46]. Furthermore, iron is a vital component of numerous cellular functions, including DNA replication and repair, and is essential for cell viability. However, dysregulated iron metabolism is associated with malignancy, cancer progression, drug resistance, and immune evasion. During radiotherapy, iron overload can induce ferroptosis in cancer cells, providing an additional anti-cancer strategy [47]. Recent studies indicate that p53, the most commonly mutated gene in human cancers, plays a significant role in radiotherapy response. Radiotherapy-mediated activation of p53 antagonizes SLC7A11 expression and represses glutathione synthesis, thereby promoting lipid peroxidation and ferroptosis. Targeting p53 may enhance radiotherapy sensitivity. Thus, ferroptosis may synergize with radiotherapy, and their combination holds promise for improving cervical cancer treatment [48]. Thus, ferroptosis may synergize with radiotherapy, and their combination holds promise for improving cervical cancer treatment.

3.2.
Role of ferroptosis in cervical cancer chemotherapy
Chemotherapy is a vital treatment for cervical cancer, with first-line agents like cisplatin and paclitaxel inducing cancer cell death through various mechanisms, including autophagy, apoptosis, and ferroptosis [49]. A study has shown that propofol exhibits a synergistic anti-cervical cancer effect with paclitaxel in cervical cancer cells, and this is achieved through the induction of apoptosis and ferroptosis mechanisms [50]. In addition, artesunate conjugated phosphorescent rhenium complexes exhibit high cytotoxicity against cancer cells lines and can induce both apoptosis and ferroptosis in HeLa cells through mitochondrial damage, caspase cascade, GSH depletion, glutathione peroxidase GPX4 inactivation and lipid peroxidation accumulation [51]. Ferroptosis, an iron-dependent lipid peroxide-driven cell death, has been recently linked to chemotherapy sensitivity [52]. A new study has shown that by combining the iron chelator desferal with platinum-based drugs, it is possible to overcome the resistance of oxaliplatin-resistant cervical cancer cells by regulating hCtr1 and TfR1 [53]. Chemotherapy drugs can synergistically induce ferroptosis through multiple pathways, including: (1) GSH depletion: Cisplatin forms Pt-GSH complexes with GSH, directly consuming GSH, causing GPX4 enzyme inactivity and reducing lipid peroxide clearance; paclitaxel oxidizes GPX4’s selenocysteine residues, weakening its antioxidant function. (2) System Xc− inhibition: Inhibiting Nrf2 nuclear translocation downregulates SLC7A11 expression, blocking cystine uptake and reducing GSH synthesis. (3) Enhanced iron metabolism: Cisplatin promotes ferritinophagy, releasing free Fe2+, upregulates TFRC, and downregulates FPN1, leading to iron overload and Fenton reaction. (4) Lipid peroxidation: Drives ACSL4 transcription to promote PUFA-PL synthesis, generating more lipid peroxides. (5) Mitochondrial dysfunction: Disrupts mitochondrial membrane potential, causing ROS bursts, triggering ferroptosis [54].

3.3.
Comparative summary of radiotherapy and chemotherapy in modulating ferroptosis pathways
Both radiotherapy and chemotherapy interact with ferroptosis pathways to enhance their cytotoxic effects on cervical cancer cells, yet they differ fundamentally in their mechanisms of ferroptosis induction and pathway modulation. Radiotherapy primarily induces ferroptosis by disrupting iron homeostasis and generating reactive oxygen species (ROS) directly through ionizing radiation, leading to lipid peroxidation and oxidative damage [55]. Its effect on suppressing GPX4 activity and amplifying intracellular ROS creates a microenvironment conducive to ferroptotic cell death, with modulation of lipid metabolism serving as a critical determinant of radiosensitivity [56]. In contrast, chemotherapy induces ferroptosis through multifaceted biochemical pathways that include the depletion of GSH, direct inhibition of antioxidant enzymes such as GPX4, and extensive remodeling of iron metabolism via ferritinophagy and altered expression of iron transporters [45]. Furthermore, chemotherapeutic agents promote lipid peroxidation by transcriptionally upregulating ACSL4 and exacerbate oxidative stress through mitochondrial dysfunction, thus triggering ferroptosis through both metabolic and signaling axes [57].
Importantly, while radiotherapy’s ferroptosis induction is closely linked to acute oxidative stress generated during radiation exposure, chemotherapy tends to invoke ferroptosis through sustained metabolic perturbations and cellular stress responses over treatment cycles [58]. This distinction may influence the timing and sequencing of combined modality therapies. Additionally, radiotherapy-induced ferroptosis appears to be more reliant on modulation of the tumor microenvironment’s redox balance, whereas chemotherapy-induced ferroptosis involves intricate crosstalk between intracellular iron metabolism, antioxidant systems, and lipid remodeling [38]. Understanding these nuanced differences offers an opportunity to optimize treatment regimens, such as combining ferroptosis sensitizers with radiotherapy to overcome radioresistance or employing targeted inhibitors of ferroptosis checkpoints alongside chemotherapy to enhance efficacy and reduce toxicity.
Collectively, appreciating the complementary yet distinct mechanisms by which radiotherapy and chemotherapy engage ferroptosis pathways can facilitate the rational design of combination therapies, leveraging ferroptosis as a critical vulnerability in cervical cancer cells. Future research should focus on elucidating the molecular determinants that dictate treatment-specific ferroptosis responsiveness to further refine personalized therapeutic strategies.

3.4.
Role of ferroptosis in cervical cancer immunotherapy
Emerging evidence underscores a significant interplay between ferroptosis and the immune system within the tumor microenvironment, which critically influences cervical cancer progression and therapeutic response. Recent studies have identified that tumor-associated macrophages (TAMs) play a pivotal role in modulating ferroptosis in cervical cancer cells. Notably, Luo [59] demonstrated that TAM-derived exosomes attenuate ferroptosis in cervical cancer by downregulating ALOX15 expression, thereby facilitating tumor cell survival and resistance to ferroptotic cell death. This highlights a mechanism through which immune cells can suppress ferroptosis, contributing to an immunosuppressive microenvironment. Furthermore, transcriptomic analyses by Yang [60] revealed that ferroptosis-related gene signatures correlate with immune microenvironment characteristics and are predictive of prognosis in cervical cancer, suggesting that ferroptosis not only affects tumor cell viability but also shapes immune infiltration and activity. Broadening these insights, Hu [61] discussed the dualistic nature of ferroptosis in tumor-associated immune cells across cancer types, describing it as a “double-edged sword” that can either potentiate antitumor immunity or promote immune evasion depending on context-specific factors. Collectively, these findings implicate ferroptosis as a critical modulator of the immune landscape in cervical cancer, presenting novel opportunities for immunotherapeutic strategies that exploit ferroptotic pathways to enhance antitumor immune responses and overcome resistance mechanisms. Future research targeting the ferroptosis-immune axis holds promise to improve immunotherapy efficacy and patient outcomes in cervical cancer.

4.
Regulatory mechanisms of ferroptosis in cervical cancer
Current research has identified various genes and molecules that can regulate ferroptosis in cervical cancer cells through multiple pathways, influencing cervical cancer’s biological behavior. These mechanisms could serve as valuable prognostic biomarkers and potential therapeutic targets in cervical cancer treatment (see Table 1 and Figure 2).
Recent advances have highlighted the critical role of ferroptosis-related genes as prognostic biomarkers in cervical cancer, providing novel insights into tumor biology and patient stratification. Han [80] identified a panel of ferroptosis-associated genes whose expression levels correlate significantly with overall survival in cervical cancer patients, suggesting their potential as reliable prognostic indicators. Their study emphasizes the utility of ferroptosis-related genes not only as markers of disease progression but also as predictors of patient outcomes, thereby facilitating personalized therapeutic strategies. Complementarily, Yu [81] classified cervical squamous cell carcinoma into distinct molecular subtypes based on ferroptosis gene expression and methylation patterns, subsequently constructing a methylation-related ferroptosis gene signature with strong prognostic value. This integrative approach underscores the importance of epigenetic regulation of ferroptosis genes in influencing tumor behavior and prognosis. Collectively, these findings support the inclusion of ferroptosis-related gene signatures in prognostic models, which may enable more accurate risk stratification and guide the development of ferroptosis-targeted therapies tailored to individual patients. Further validation of these biomarkers in large, independent cohorts will be essential to translate these models into clinical practice.
In recent years, the crosstalk among various cell death pathways has emerged as a cutting-edge topic in tumor research. Recent studies reveal complex interactions between ferroptosis and other novel cell death forms such as cuproptosis, which hold notable significance in immunotherapy and mRNA vaccine development [82]. Ferroptosis is an iron-dependent cell death driven by lipid peroxidation, whereas cuproptosis relies on copper-induced aberrant lipoylation of mitochondrial proteins and subsequent protein aggregation. These two modalities potentially influence cellular metabolism and metal ion homeostasis in an interconnected manner [83]. Such crosstalk among cell death forms may impact immune cell activation and inflammatory responses within the tumor microenvironment, thereby modulating tumor immune evasion. Especially in mRNA-based immunotherapeutic strategies, balancing ferroptosis and cuproptosis regulation may enhance antitumor immune responses and improve therapeutic efficacy [84]. Furthermore, the interplay between ferroptosis and classical programmed cell death pathways, including apoptosis, autophagy, and necroptosis, offers novel insights into tumor cell survival and mechanisms of therapy resistance. Collectively, in-depth investigation of the molecular interactions between ferroptosis and other cell death modalities, as well as their roles in immunotherapy, not only enriches the theoretical framework of cell death but also provides innovative directions and research opportunities for developing multi-targeted synergistic therapies to enhance cervical cancer treatment outcomes.

5.
Limitations and future directions
Despite ongoing research, several challenges remain: (1) HPV Infection Microenvironment: The dynamic influence of the HPV infection microenvironment on ferroptosis-related pathways requires further investigation. HPV proteins, such as E6 and E7, not only alter host cell cycle control and induce genomic instability but also modulate key signaling pathways involved in ferroptosis, including p53 and mTOR. The precise mechanisms through which HPV modulates these pathways and affects ferroptosis sensitivity need to be delineated through extensive molecular studies and clinical correlates. Understanding these interactions could inform the development of therapeutic strategies that exploit HPV-induced vulnerabilities. (2) Tissue Specificity of Ferroptosis Inducers: Existing ferroptosis inducers lack tissue specificity, which may lead to systemic iron overload, hepatotoxicity, and off-target effects. For example, Erastin and RSL3, widely studied ferroptosis inducers, can accumulate in non-cancerous tissues, potentially causing unwanted side effects. To overcome this, research should focus on designing ferroptosis inducers conjugated to tumor-specific ligands or antibodies, thereby enhancing their selectivity. Additionally, prodrugs that are selectively activated in the tumor microenvironment may provide a solution to mitigate systemic toxicity. (3) Clinical Translation and Standardization: Clinical translation of ferroptosis-based therapies in cervical cancer remains in its infancy. The absence of standardized detection systems for ferroptosis biomarkers in clinical settings poses a significant barrier. Advances in biosensing technologies and artificial intelligence could be harnessed to develop non-invasive detection tools. Standardization of assays for biomarkers such as GPX4, SLC7A11, and ACSL4 is essential for clinical applications. Furthermore, creating a repository of ferroptosis-related genetic and proteomic profiles from a large cohort of cervical cancer patients would facilitate personalized treatment approaches. Future research should focus on: (1) Interaction with the Immune Microenvironment: The interaction between ferroptosis and the immune microenvironment in cervical cancer is an area of high therapeutic potential. Ferroptotic cell death releases damage-associated molecular patterns (DAMPs) and may enhance anti-tumor immunity by recruiting and activating dendritic cells, T cells, and macrophages. Exploring the combination of ferroptosis inducers with immune checkpoint inhibitors like anti-PD-1/PD-L1 or CTLA-4 antibodies could potentiate this effect. Clinical trials such as NCT04439291 are investigating this synergy, and preclinical models indicate that tumor ferroptosis can transform “cold” tumors into “hot” ones, thereby enhancing susceptibility to immunotherapy. (2) Nanocarrier-Targeted Delivery Systems: Nanocarrier-targeted delivery systems represent a promising approach to enhance the delivery and efficacy of ferroptosis inducers while minimizing off-target effects. Emerging nanocarrier platforms, such as liposomes, polymeric nanoparticles, metal-organic frameworks, and hybrid nanomaterials, have shown potential in preclinical studies for encapsulating ferroptosis inducers. Additionally, stimuli-responsive nanocarriers that release their payload in response to the tumor microenvironment’s acidic pH or specific enzymes can further increase treatment precision. (3) Multicenter Clinical Trials: Comprehensive multicenter clinical trials are indispensable to validate the clinical utility of ferroptosis-related genes as predictive markers for therapeutic responses in cervical cancer. Trials should include diverse patient populations and standardized protocols to evaluate the safety, efficacy, and pharmacokinetics of ferroptosis inducers. Furthermore, advanced imaging modalities, such as positron emission tomography (PET) with novel tracers specific for ferroptotic cells, can provide real-time insights into treatment efficacy and tumor response. Collaborative efforts between academic institutions, pharmaceutical companies, and healthcare providers will be crucial in translating these findings into clinical practice.
By addressing these limitations through targeted research and clinical validation, ferroptosis-related therapies have the potential to revolutionize cervical cancer treatment and improve patient outcomes. The integration of molecular insights, advanced delivery systems, and robust clinical trials will pave the way for the successful application of ferroptosis in clinical oncology.

6.
Conclusion
In summary, ferroptosis-targeted therapeutic strategies provide a new breakthrough for cervical cancer treatment. Moreover, an in-depth analysis of the regulatory mechanisms of ferroptosis not only expands our understanding of the biological behavior of cervical cancer but also offers a theoretical basis for overcoming treatment challenges in advanced/recurrent cervical cancer. By integrating molecular mechanism research, technological innovation, and clinical translation, ferroptosis-targeted therapeutic strategies are expected to become an essential component of precision medicine for cervical cancer.