Circ_BBS9 as an early diagnostic biomarker for lung adenocarcinoma: direct interaction with IFIT3 in the modulation of tumor immune microenvironment.

Background: Introduction: Circular RNAs (circRNAs) have been identified as significant contributors to the development and advancement of cancer. The objective of this study was to examine the expression and clinical implications of circRNA circ_BBS9 in lung adenocarcinoma (LUAD), as well as its potential modes of action. Methods: The expression of Circ_BBS9 was examined in tissues and cell lines of LUAD through the utilization of microarray profiling, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. In this study, we assessed the impact of circ_BBS9 on the proliferation of LUAD cells, as well as its influence on ferroptosis and tumor formation. To analyze these effects, we employed CCK-8 assays and ferroptosis assays. The identification of proteins that interact with Circ_BBS9 was achieved through the utilization of RNA pull-down and mass spectrometry techniques. A putative regulatory network comprising circ_BBS9, miR-7150, and IFIT3 was established using bioinformatics study. The investigation also encompassed the examination of the correlation between the expression of IFIT3 and the invasion of immune cells. Results: Circ_BBS9 was significantly downregulated in LUAD tissues and cell lines. Low circ_BBS9 expression correlated with poor prognosis. Functional experiments showed that circ_BBS9 overexpression inhibited LUAD cell proliferation and promoted ferroptosis in vitro and suppressed tumor growth in vivo. Mechanistically, circ_BBS9 was found to directly interact with IFIT3 and regulate its expression by acting as a sponge for miR-7150. Additionally, IFIT3 expression correlated positively with immune infiltration in LUAD. Conclusion: Circ_BBS9 has been identified as a tumor suppressor in lung adenocarcinoma (LUAD) and holds promise as a diagnostic biomarker. The potential mechanism of action involves the modulation of ferroptosis and the immunological microenvironment through direct interaction with IFIT3 and competitive binding to miR-7150. The aforementioned findings offer new perspectives on the pathophysiology of LUAD and highlight circ_BBS9 as a potentially valuable target for therapeutic interventions.

Investigation of ferroptosis-associated molecular subtypes and immunological characteristics in lupus nephritis based on artificial neural network learning.

BACKGROUND: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) with poor treatment outcomes. The role and underlying mechanisms of ferroptosis in LN remain largely unknown. We aimed to explore ferroptosis-related molecular subtypes and assess their prognostic value in LN patients. METHODS: Molecular subtypes were classified on the basis of differentially expressed ferroptosis-related genes (FRGs) via the Consensus ClusterPlus package. The enriched functions and pathways, immune infiltrating levels, immune scores, and immune checkpoints were compared between the subgroups. A scoring algorithm based on the subtype-specific feature genes identified by artificial neural network machine learning, referred to as the NeuraLN, was established, and its immunological features, clinical value, and predictive value were evaluated in patients with LN. Finally, immunohistochemical analysis was performed to validate the expression and role of feature genes in glomerular tissues from LN patients and controls. RESULTS: A total of 10 differentially expressed FRGs were identified, most of which showed significant correlation. Based on the 10 FRGs, LN patients were classified into two ferroptosis subtypes, which exhibited significant differences in immune cell abundances, immune scores, and immune checkpoint expression. A NeuraLN-related protective model was established based on nine subtype-specific genes, and it exhibited a robustly predictive value in LN. The nomogram and calibration curves demonstrated the clinical benefits of the protective model. The high-NeuraLN group was closely associated with immune activation. Clinical specimens demonstrated the alterations of ALB, BHMT, GAMT, GSTA1, and HAO2 were in accordance with bioinformatics analysis results, GSTA1 and BHMT were negatively correlated with the severity of LN. CONCLUSION: The classification of ferroptosis subtypes and the establishment of a protective model may form a foundation for the personalized treatment of LN patients.

Unraveling the role of sulfiredoxin-1 in early-onset preeclampsia: A key player in trophoblast ferroptosis.

Preeclampsia (PE) significantly contributes to obstetric complications and maternal mortality, yet its pathogenesis and mechanisms are not well understood. Sulfiredoxin-1 (SRXN1) is known for its antioxidant activity and its role in defending against oxidative stress; it is also linked to various cancers. However, the role of SRXN1 in PE remains unclear. Our study found a significant decrease in SRXN1 levels in the serum and placental tissues of patients with early-onset preeclampsia (EOPE). Similarly, a PE-like mouse model showed reduced SRXN1 expression. Our in vitro experiments showed that reducing SRXN1 impaired trophoblast viability, decreased invasion and migration, and led to cell death, primarily through ferroptosis. These results are consistent with analyses of placental tissues from EOPE patients. In summary, lower SRXN1 levels during pregnancy contribute to trophoblast ferroptosis, potentially affecting the development and progression of EOPE.

[Research progress on ferroptosis in tumor immunity].

Ferroptosis is a novel form of cell death that is induced by excessive accumulation of ferrous ions and lipid peroxides. It triggers the release of damage-associated molecular patterns through autophagy-dependent mechanisms, serving as an adjunct to immunogenic cell death and activating both adaptive and innate immunity. In the tumor microenvironment, the regulation and influence of tumor cells and immune cells undergoing ferroptosis are regulated by various factors, which plays a crucial role in tumor development, treatment, and prognosis. This article provides an overview of the biological effects of ferroptosis on immune cells such as T cells, macrophages, neutrophils and B cells and tumor cells in the tumor microenvironment.

Ironing out the role of ferroptosis in immunity.

Ferroptosis is a type of regulated cell death that drives the pathophysiology of many diseases. Oxidative stress is detectable in many types of regulated cell death, but only ferroptosis involves lipid peroxidation and iron dependency. Ferroptosis originates and propagates from several organelles, including the mitochondria, endoplasmic reticulum, Golgi, and lysosomes. Recent data have revealed that immune cells can both induce and undergo ferroptosis. A mechanistic understanding of how ferroptosis regulates immunity is critical to understanding how ferroptosis controls immune responses and how this is dysregulated in disease. Translationally, more work is needed to produce ferroptosis-modulating immunotherapeutics. This review focuses on the role of ferroptosis in immune-related diseases, including infection, autoimmune diseases, and cancer. We discuss how ferroptosis is regulated in immunity, how this regulation contributes to disease pathogenesis, and how targeting ferroptosis may lead to novel therapies.

Non-apoptotic regulated cell death mediates reprogramming of the tumour immune microenvironment by macrophages.

Tumour immune microenvironment (TIME) plays an indispensable role in tumour progression, and tumour-associated macrophages (TAMs) are the most abundant immune cells in TIME. Non-apoptotic regulated cell death (RCD) can avoid the influence of tumour apoptosis resistance on anti-tumour immune response. Specifically, autophagy, ferroptosis, pyroptosis and necroptosis mediate the crosstalk between TAMs and tumour cells in TIME, thus reprogram TIME and affect the progress of tumour. In addition, although some achievements have been made in immune checkpoint inhibitors (ICIs), there is still defect that ICIs are only effective for some people because non-apoptotic RCD can bypass the apoptosis resistance of tumour. As a result, ICIs combined with targeting non-apoptotic RCD may be a promising solution. In this paper, the basic molecular mechanism of non-apoptotic RCD, the way in which non-apoptotic RCD mediates crosstalk between TAMs and tumour cells to reprogram TIME, and the latest research progress in targeting non-apoptotic RCD and ICIs are reviewed.

A preliminary study unveils CISD2 as a ferroptosis-related therapeutic target for recurrent spontaneous abortion through immunological analysis and two-sample mendelian randomization.

Recurrent spontaneous abortion (RSA) affects approximately 1 % of women striving for conception, posing a significant clinical challenge. This study aimed to identify a prognostic signature in RSA and elucidate its molecular mechanisms. Prognostic gene impacts were further assessed in HTR-8/SVneo and human primary extravillous trophoblast (EVT) cells in vitro experiments. A total of 6168 differentially expressed genes (DEGs) were identified, including 3035 upregulated and 3133 downregulated genes. WGCNA pinpointed 8 significant modules and 31 ferroptosis-related DEGs in RSA. Optimal clustering classified RSA patients into three distinct subgroups, showing notable differences in immune cell composition. Six feature genes (AEBP2, CISD2, PML, RGS4, SRSF9, STK11) were identified. The diagnostic model showed high predictive capabilities (AUC: 0.966). Mendelian randomization indicated a significant association between CISD2 levels and RSA (OR: 1.069, P-value: 0.049). Furthermore, the downregulation of CISD2 promotes ferroptosis in HTR-8/SVneo and human primary EVT cells. CISD2 emerged as a pivotal gene in RSA, serving as a ferroptosis-related therapeutic target. The diagnostic model based on gene expression and Mendelian randomization provides novel insights into the pathogenesis of RSA.

The new era of lung cancer therapy: Combining immunotherapy with ferroptosis.

Ferroptosis is an unconventional programmed cell death mode caused by phospholipid peroxidation dependent on iron. Emerging immunotherapies (especially immune checkpoint inhibitors) have the potential to enhance lung cancer patients' long-term survival. Although immunotherapy has yielded significant positive applications in some patients, there are still many mechanisms that can cause lung cancer cells to evade immunity, thus leading to the failure of targeted therapies. Immune-tolerant cancer cells are insensitive to conventional death pathways such as apoptosis and necrosis, whereas mesenchymal and metastasis-prone cancer cells are particularly vulnerable to ferroptosis, which plays a vital role in mediating immune tolerance resistance by tumors and immune cells. As a result, triggering lung cancer cell ferroptosis holds significant therapeutic potential for drug-resistant malignancies. Here, we summarize the mechanisms underlying the suppression of ferroptosis in lung cancer, highlight its function in the lung cancer immune microenvironment, and propose possible therapeutic strategies.

Immunogenicity of ferroptosis in cancer: a matter of context?

Ferroptosis is a variant of regulated cell death (RCD) elicited by an imbalance of cellular redox homeostasis that culminates with extensive lipid peroxidation and rapid plasma membrane breakdown. Since other necrotic forms of RCD, such as necroptosis, are highly immunogenic, ferroptosis inducers have attracted considerable attention as potential tools to selectively kill malignant cells while eliciting therapeutically relevant tumor-targeting immune responses. However, rather than being consistently immunogenic, ferroptosis mediates context-dependent effects on anticancer immunity. The inability of ferroptotic cancer cells to elicit adaptive immune responses may arise from contextual deficiencies in intrinsic aspects of the process, such as adjuvanticity and antigenicity, or from microenvironmental defects imposed by ferroptotic cancer cells themselves or elicited by the induction of ferroptosis in immune cells.

Epstein-Barr virus latency programs dynamically sensitize B cells to ferroptosis.

SignificanceEpstein-Barr virus (EBV) contributes to Burkitt lymphoma and post-transplant lymphoproliferative disease (PTLD). EBV-transforming programs activate lipid metabolism to convert B cells into immortalized lymphoblastoid cell lines (LCL), a PTLD model. We found that stages of EBV transformation generate lipid reactive oxygen species (ROS) byproducts to varying degrees, and that a Burkitt-like phase of B cell outgrowth requires lipid ROS detoxification by glutathione peroxidase 4 and its cofactor glutathione. Perturbation of this redox defense in early stages of transformation or in Burkitt cells triggered ferroptosis, a programmed cell death pathway. LCLs were less dependent on this defense, a distinction tied to EBV latency programs. This highlights ferroptosis induction as a potential therapeutic approach for prevention or treatment of certain EBV+ lymphomas.

Tumour cells are sensitised to ferroptosis via RB1CC1-mediated transcriptional reprogramming.

BACKGROUND: Ferroptosis, a form of regulated cell death, is an important topic in the field of cancer research. However, the signalling pathways and factors that sensitise tumour cells to ferroptosis remain elusive. METHODS: We determined the level of ferroptosis in cells by measuring cell death and lipid reactive oxygen species (ROS) production. The expression of RB1-inducible coiled-coil 1 (RB1CC1) and related proteins was analyzed by immunoblotting and immunohistochemistry. Immunofluorescence was used to determine the subcellular localization of RB1CC1. We investigated the mechanism of RB1CC1 nuclear translocation by constructing a series of RB1CC1 variants. To examine the ferroptosis- and RB1CC1-dependent transcriptional program in tumour cells, chromatin immunoprecipitation sequencing was performed. To assess the effect of c-Jun N-terminal kinase (JNK) agonists on strenthening imidazole ketone erastin (IKE) therapy, we constructed cell-derived xenograft mouse models. Mouse models of hepatocellular carcinoma to elucidate the importance of Rb1cc1 in IKE-based therapy of liver tumourigenesis. RESULTS: RB1CC1 is upregulated by lipid ROS and that nuclear translocation of phosphorylation of RB1CC1 at Ser537 was essential for sensitising ferroptosis in tumour cells. Upon ferroptosis induction, nuclear RB1CC1 sharing forkhead box (FOX)-binding motifs recruits elongator acetyltransferase complex subunit 3 (ELP3) to strengthen H4K12Ac histone modifications within enhancers linked to ferroptosis. This also stimulated transcription of ferroptosis-associated genes, such as coiled-coil-helix-coiled-coil-helix domain containing 3 (CHCHD3), which enhanced mitochondrial function to elevate mitochondrial ROS early following induction of ferroptosis. FDA-approved JNK activators reinforced RB1CC1 nuclear translocation and sensitised cells to ferroptosis, which strongly suggested that JNK is upstream of RB1CC1. Nuclear localisation of RB1CC1 correlated with lipid peroxidation in clinical lung cancer specimens. Rb1cc1 was essential for ferroptosis agonists to suppress liver tumourigenesis in mice. CONCLUSIONS: Our findings indicate that RB1CC1-associated signalling sensitises tumour cells to ferroptosis and that targeting RB1CC1 may be beneficial for tumour treatment.

Integrative analysis of the molecular mechanisms, immunological features and immunotherapy response of ferroptosis regulators across 33 cancer types.

Ferroptosis is a recently described mode of cell death caused by the accumulation of intracellular iron and lipid reactive oxygen species (ROS), which play critical roles in tumorigenesis and cancer progression. However, the underlying molecular mechanisms and promising biomarkers of ferroptosis among cancers remain to be elucidated. In this study, 30 ferroptosis regulators in ferroptosis-related signaling pathways were identified and analyzed in 33 cancer types. We found transcriptomic aberrations and evaluated the prognostic value of ferroptosis regulators across 33 cancer types. Then, we predicted and validated potential transcription factors (including E2F7, KLF5 and FOXM1) and therapeutic drugs (such as cyclophosphamide, vinblastine, and gefitinib) that target ferroptosis regulators in cancer. Moreover, we explored the molecular mechanisms of ferroptosis and found that signaling pathways such as the IL-1 and IL-2 pathways are closely associated with ferroptosis. Additionally, we found that ferroptosis regulators have a close relationship with immunity-related parameters, including the immune score, immune cell infiltration level, and immune checkpoint protein level. Finally, we determined a ferroptosis score using GSVA method. We found that the ferroptosis score effectively predicted ferroptotic cell death in tumor samples. And ferroptosis score is served as an independent prognostic indicator for the incidence and recurrence of cancers. More importantly, patients with high ferroptosis scores received greater benefit from immunotherapy. We aslo created an online webserver based on the nomogram prognostic model to predict the survival in immunotherapy cohort. The reason for this outcome is partially the result of patients with a high ferroptosis rate also having high immune scores, HLA-related gene expression and immune checkpoint protein expression, such as PDL2 and TIM3. Moreover, patients with high ferroptosis scores exhibited CD8 T cell and TIL infiltration and immune-related signaling pathway enrichment. In summary, we systematically summarize the molecular characteristics, clinical relevance and immune features of ferroptosis across cancers and show that the ferroptosis score can be used as a prognostic factor and for the evaluation of immunotherapy effects.

The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3ß kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2-AKT-GSK3ß axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Identification of immune subtypes of Ph-neg B-ALL with ferroptosis related genes and the potential implementation of Sorafenib.

BACKGROUND: The clinical outcome of Philadelphia chromosome-negative B cell acute lymphoblastic leukemia (Ph-neg B-ALL) varies considerably from one person to another after clinical treatment due to lack of targeted therapies and leukemia's heterogeneity. Ferroptosis is a recently discovered programmed cell death strongly correlated with cancers. Nevertheless, few related studies have reported its significance in acute lymphoblastic leukemia. METHODS: Herein, we collected clinical data of 80 Ph-neg B-ALL patients diagnosed in our center and performed RNA-seq with their initial bone marrow fluid samples. Throughout unsupervised machine learning K-means clustering with 24 ferroptosis related genes (FRGs), the clustered patients were parted into three variant risk groups and were performed with bioinformatics analysis. RESULTS: As a result, we discovered significant heterogeneity of both immune microenvironment and genomic variance. Furthermore, the immune check point inhibitors response and potential implementation of Sorafenib in Ph-neg B-ALL was also analyzed in our cohort. Lastly, one prognostic model based on 8 FRGs was developed to evaluate the risk of Ph-neg B-ALL patients. CONCLUSION: Jointly, our study proved the crucial role of ferroptosis in Ph-neg B-ALL and Sorafenib is likely to improve the survival of high-risk Ph-neg B-ALL patients.

Isoliquiritigenin attenuates septic acute kidney injury by regulating ferritinophagy-mediated ferroptosis.

Defined differently from apoptosis, necrosis, and autophagy, ferroptosis has been implicated in acute kidney injury (AKI) such as ischemia-reperfusion injury induced AKI, folic acid caused AKI and cisplatin induced AKI. However, whether ferroptosis is involved in LPS induced AKI could be remaining unclear and there is still a lack of therapies associated with ferroptosis in LPS induced AKI without side effects. This study aimed to elucidate the role of isoliquiritigenin (ISL) in ferroptosis of LPS-induced AKI. We used LPS to induce renal tubular injury, followed by treatment with ISL both in vitro and in vivo. Human renal tubular HK2 cells were pretreated with 50 µM or 100 µM ISL for 5 h before stimulation with 2 µg/mL LPS. Mice were administered a single dose of either 50 mg/kg ISL orally or 5 mg/kg ferroptosis inhibitor ferrostatin-1 intraperitoneally before 10 mg/kg LPS injection. We found that LPS could induce mitochondria injury of renal tubular presented as the shape of mitochondria appeared smaller than normal with increased membrane density and are faction or destruction of mitochondrial crista through scanning electron microscope. Ferrostatin-1 significantly protected mice against renal dysfunction and renal tubular damage in LPS-induced AKI. ISL inhibited Fe2+ and lipid peroxidation accumulation in LPS-stimulated HK2 cells. It also increased the expression of GPX4 and xCT, reduced the expression of HMGB1 and NCOA4 then attenuated mitochondria injury in renal tubular following LPS stimulation. These results indicated the potential role of ISL against ferritinophagy-mediated ferroptosis in renal tubular following LPS stimulation.

Ferroportin-mediated ferroptosis involved in new-onset atrial fibrillation with LPS-induced endotoxemia.

Sepsis is a known risk factor for new-onset atrial fibrillation (AF), and previous studies have demonstrated that ferroptosis participates in sepsis-induced organ injury development. Nevertheless, the role of ferroptosis in new-onset AF with sepsis remains largely unknown. This study aims to investigate the underlying mechanisms linking ferroptosis and AF caused by sepsis. LPS-induced endotoxemia is often used to model the acute inflammatory response associated with sepsis. Herein, we reported that ferroptosis was significantly activated in LPS-induced endotoxemia rat model. We also observed that ferroportin (Fpn), the only identified mammalian non-heme iron exporter, was downregulated in the atrium of endotoxemia model. Vulnerability to AF was also significantly increased in a endotoxemia rat model. Additionally, Fpn knockdown by shFpn further increased intracellular iron concentration and oxidative stress and exaggerated the AF vulnerability, which was alleviated by ferroptosis inhibition. Mechanistically, silencing Fpn worsened the alterations in calcium handling proteins expression in a endotoxemia rat model. These findings suggest that Fpn-mediated ferroptosis is involved in the new-onset AF with LPS-induced endotoxemia via worsening the calcium handling proteins dysregulation and provides a novel and promising strategy for preventing AF development in sepsis.

A nanounit strategy reverses immune suppression of exosomal PD-L1 and is associated with enhanced ferroptosis.

In addition to increasing the expression of programmed death-ligand 1 (PD-L1), tumor cells can also secrete exosomal PD-L1 to suppress T cell activity. Emerging evidence has revealed that exosomal PD-L1 resists immune checkpoint blockade, and may contribute to resistance to therapy. In this scenario, suppressing the secretion of tumor-derived exosomes may aid therapy. Here, we develop an assembly of exosome inhibitor (GW4869) and ferroptosis inducer (Fe3+) via amphiphilic hyaluronic acid. Cooperation between the two active components in the constructed nanounit induces an anti-tumor immunoresponse to B16F10 melanoma cells and stimulates cytotoxic T lymphocytes and immunological memory. The nanounit enhances the response to PD-L1 checkpoint blockade and may represent a therapeutic strategy for enhancing the response to this therapy.

Targeted therapy for drug-tolerant persister cells after imatinib treatment for gastrointestinal stromal tumours.

BACKGROUND: Despite the effectiveness of tyrosine kinase inhibitors (TKI), gastrointestinal stromal tumours (GIST) develop after the withdrawal of TKI. Based on previous studies, a subpopulation of drug-tolerant cells called "persister cells" may be responsible for the recurrence and have thus, gained attention as a novel target in cancer therapy. METHODS: The metabolic changes were investigated in imatinib-derived persister GIST cells. We investigated the efficacy and the mechanism of GPX4 inhibitor, which is known as a major inducer of "ferroptosis". We also evaluated the effects of RSL3 to the gefitinib-derived persister lung cancer cells. RESULTS: We demonstrated a downregulation of glucose metabolism, subsequent decrease in the glutathione level and sensitivity to glutathione peroxidase 4 (GPX4) inhibitor, RSL3 in persister cells. As the cell death induced by RSL3 was found to be "iron-dependent" and "caspase-independent", loss of GPX4 function could have possibly induced selective persister cell ferroptotic death. In the xenograft model, we confirmed the inhibition of tumour regrowth after discontinuation of imatinib treatment. Moreover, RSL3 prevented the growth of gefitinib-derived persister lung cancer cells. CONCLUSIONS: RSL3 combined with TKI may be a promising therapy for both GIST and epidermal growth factor receptor-mutated lung cancer.

Ferroptosis: A New Promising Target for Lung Cancer Therapy.

Ferroptosis is a new type of regulatory cell death that differs from autophagy, apoptosis, necrosis, and pyroptosis; it is caused primarily by the accumulation of iron and lipid peroxides in the cell. Studies have shown that many classical signaling pathways and biological processes are involved in the process of ferroptosis. In recent years, investigations have revealed that ferroptosis plays a crucial role in the progression of tumors, especially lung cancer. In particular, inducing ferroptosis in cells can inhibit the growth of tumor cells, thereby reversing tumorigenesis. In this review, we summarize the characteristics of ferroptosis from its underlying basis and role in lung cancer and provide possible applications for it in lung cancer therapies.

Development and validation of a ferroptosis-related prognostic model for the prediction of progression-free survival and immune microenvironment in patients with papillary thyroid carcinoma.

BACKGROUND: Ferroptosis is an iron-dependent and regulated cell death that has been widely reported in a variety of malignancies. The overall survival of papillary thyroid cancer (PTC) is excellent, but the identification of patients with poor prognosis still faces challenges. Nevertheless, whether ferroptosis-related genes (FRGs) can be used to screen high-risk patients is not clear. METHODS: We obtained the clinical data of patients with PTC and FRGs from the UCSC Xena platform and the FerrDb respectively. Differentially expressed genes (DEGs) of FRGs were obtained from the entire The Cancer Genome Atlas (TCGA). Subsequently, the entire TCGA dataset was randomly split into two subsets: training and test datasets. Based on DEGs, we constructed a predictive model which was tested in the test dataset and the entire TCGA dataset to predict progression-free survival (PFS). Patients were categorized into high- or low-risk groups based on their median risk score. We analyzed differences in some aspects, including pathway enrichment analysis, single-sample Gene Set Enrichment Analysis (ssGSEA), tumor microenvironment (TME), human leukocyte antigen (HLA) genes, and tumor mutation burden (TMB) analyses, between high-risk and low-risk groups. RESULTS: A predictive model with three FRGs (HSPA5, AURKA, and TSC22D3) was constructed. Patients in the high-risk group had worse PFS compared with patients in the low-risk group. Functional analysis results revealed that ssGSEA, immune cell infiltration, TME, HLA, and TMB were closely associated with ferroptosis. CONCLUSION: The prognostic model constructed in this study can effectively predict PFS for patients with PTC.