PURPOSE:This narrative review aims to elucidate the interconnections between ionizing radiation (IR)-induced oxidative base modification(s) and gene expression reprogramming that promote tissue repair, driving lung fibrosis and ultimately resulting in life-threatening organ dysfunction with limited therapeutic options. CONCLUSIONS:IR introduces diverse chemical modifications into chromatin, affecting both histones and DNA, both directly or indirectly through reactive oxygen and nitrogen species. Among DNA bases, guanine -an electron-rich heterocycle-is the most susceptible to oxidation, primarily forming 8-oxo-7,8-dihydroguanine (8-oxoGua). Long regarded solely as a mutagenic biomarker of oxidative stress, 8-oxoGua is now recognized as an epigenetic-like mark that serves as a platform for anchoring 8-oxoguanine DNA glycosylase 1 (OGG1), that interacts with both chromatin remodelers and transcription factors, thus, promoting essential transcription initiation complex assembly. In this capacity, the OGG1 repairactome acts as a signaling hub rather than merely an initiator of base excision repair and is essential for transcriptional reprogramming toward controlled and/or unrestrained inflammatory and profibrotic programs. These include those mediated by TGF-β/SMAD signaling that drives myofibroblast differentiation and extracellular matrix deposition in promoting tissue repair. Notably, pharmacological inhibition of OGG1 repairactome formation markedly attenuates pulmonary pathologies induced by the radiomimetic agent bleomycin or by TGF-β1, thereby preserving and improving lung function in experimental models.

PURPOSE:Mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a well-documented environmental endocrine disruptor with estrogen-like effects that promote the development of hormone receptor-positive tumors. G protein-coupled receptor 30 (GPR30), also known as G protein-coupled estrogen receptor 1, has emerged as a key factor in the pathogenesis and progression of hormone-dependent tumors. This study elucidates the mechanism by which MEHP promotes breast cancer development via GPR30. METHODS:MCF-7 cells were exposed to different concentrations of MEHP, and GPR30 expression was inhibited using G15. Cell proliferation and cell cycle were assessed using the CCK-8 and flow cytometry, respectively. Cell migration and cell invasion were evaluated via scratch-wound assays and transwell migration assay. Western blotting and quantitative real-time reverse transcription PCR were performed to analyze the expression of GPR30 and epithelial-mesenchymal transition (EMT)-related mRNAs and proteins. RESULTS:Our findings demonstrate that MEHP exposure promotes the proliferation, migration, and invasion of MCF-7 cells, while concomitantly modulating the expression of GPR30, cell cycle-related and EMT-associated mRNAs and proteins. After inhibiting GPR30, the promoting effect of MEHP on MCF-7 cell proliferation and migration decreased. CONCLUSION:Notably, GPR30 inhibition attenuated MEHP-induced promotion of MCF-7 cell proliferation and migration through modulating the EMT process.

Radiation-induced lung injury (RILI) is a serious complication of thoracic radiotherapy, with limited effective treatment options. This study demonstrates that fecal microbiota transplantation (FMT) confers protection against RILI through modulation of the gut-lung axis. In a total lung irradiation (TLI) mouse model, FMT significantly alleviated pulmonary histopathological injury, inflammatory responses, oxidative stress, and collagen deposition during fibrogenesis. Concurrently, FMT improved intestinal motility, enhanced mucosal barrier integrity, and restored TLI-induced dysbiosis in gut microbiota diversity and community structure. Metabolomic analysis revealed that TLI significantly disrupted the metabolism of unsaturated fatty acids and arachidonic acid (AA), whereas FMT partially restored these metabolic networks. Transcriptomic and ultrastructural analyses indicated that RILI suppressed endoplasmic reticulum (ER) protein processing and induced ER swelling, while FMT promoted protective ER-phagy and facilitated restoration of ER morphology. Integrated multi-omics analysis further identified the AA metabolism as a key component of FMT-mediated protection, with its alterations closely associated with pulmonary tissue repair. Further in vivo and in vitro experiments demonstrated that AA binds to and activates the nuclear receptor PPARγ, leading to transcriptional upregulation of FAM134B, promoting protective ER-phagy and ameliorating RILI. In summary, this study highlights the bidirectional gut-lung axis as a therapeutic target in RILI progression and intervention, and reveals that FMT confers protection through metabolic remodeling and activation of the PPARγ-FAM134B-mediated ER-phagy pathway, providing a mechanistic basis for potential clinical translation.

Radiation-induced pulmonary fibrosis, a devastating thoracic radiotherapy sequela, features aberrant ECM deposition and irreversible loss of functional lung architecture. However, the exact molecular mechanisms governing AECII dysfunction and fate transition during RIPF remain poorly understood. Here, we identify a novel metabolic-epigenetic-epitranscriptomic cascade that orchestrates the pro-fibrotic fate of AECIIs. We demonstrate that radiation exposure triggers a glycolytic shift in AECIIs, resulting in pathological intracellular lactate accumulation. This metabolic stress is directly coupled to chromatin remodeling via p300-mediated H3K18la at the VIRMA promoter, driving its robust transcriptional activation. Consequently, elevated VIRMA promotes a pro-fibrotic epitranscriptomic landscape by increasing m6A enrichment on the GATA3 mRNA. Recognition of this modification by the m6A reader YTHDF1 extends GATA3 mRNA half-life. The ensuing GATA3 accumulation initiates EMT and exacerbates ECM deposition. Strikingly, utilizing AECII-specific Virma conditional knockout mice, we confirmed the essential role of this axis in vivo; genetic ablation of Virma preserved alveolar integrity and conferred resistance to radiation-induced fibrogenesis. Furthermore, pharmacological inhibition of the H3K18la writer p300 using C646 abrogated the fibrotic phenotype. Collectively, our findings elucidate how radiation-induced metabolic reprogramming is durably inscribed into the epigenome to dictate cell fate, offering a therapeutic rationale for targeting the H3K18la/VIRMA/GATA3 axis in RIPF.

Radiation-induced injury remains a significant challenge in the radiotherapy of cancer patients. Ionizing radiation causes various cellular and molecular damages, leading to both acute and chronic organ dysfunction. Its impact extends beyond interrupting standard treatment protocols and adversely affects the quality of life. Therefore, understanding the mechanisms underlying radiation-induced injury and identifying effective treatment strategies are crucial. In this review, we summarize the recent advances in the molecular and cellular mechanisms of radiation-induced injury across various organs and systems, particularly in the lung, gastrointestinal system, brain, skin, and bone. We highlight the roles of oxidative stress, DNA damage response, mitochondrial dysfunction, and epigenetics in radiation pathology, and summarize the relevant signaling pathways and cellular responses involved in radiation damage. Additionally, we discuss the common symptoms, risk factors, and current diagnostic strategies of radiation-induced injuries. Furthermore, this article provides an in-depth review of effective clinical treatments, elucidates their mechanisms of action, and highlights emerging therapeutic approaches, such as stem cell therapy, nanomedicine, and exosome-based interventions, in clinical practice. Despite significant advances in understanding radiation-induced injury, challenges remain in translating molecular insights into effective therapies. The review concludes with a call for integrated, precision medicine-based approaches to better manage radiation-induced injuries and improve patient outcomes.

[This corrects the article DOI: 10.3389/fimmu.2024.1467151.].

GTPase IMAP family member 8 (GIMAP8) plays a key role in pathophysiology of several malignancies. The objective of this current research endeavor was to investigate the prognosis value of GIMAP8 in lung adenocarcinoma and examine how it relates to immunity. Expression profiles associated with GIMAP8 and related clinical details were acquired from The Cancer Genome Atlas database, and we conducted survival analysis, enrichment analysis and immune infiltration studies. Additionally, we evaluated the effect of GIMAP8 on radiation resistance of tumor by in vivo and in vitro experiments. Our results showed that lung adenocarcinoma tumor tissues exhibited lower GIMAP8 levels compared to nearby normal tissues. Furthermore, decreased GIMAP8 expression strongly correlated with poorer OS. The expression of GIMAP8 is closely related to the formation of radiation resistance in tumor cells. GSEA identified multiple signaling pathways linked to GIMAP8, including immune-related, chemokine, cell adhesion molecule, and NF-κB signaling pathways. GIMAP8 expression strongly correlated with the expression of immune checkpoint molecules, tumor mutational burden, tumor neoantigen burden, immune cells, and tumor immune microenvironment. GIMAP8 was found to have an inhibitory effect on lung adenocarcinoma and was closely related to the immune response. Moreover, GIMAP8 may also influence radiation resistance in tumors.

Radiotherapy is a cornerstone treatment for non-small cell lung cancer (NSCLC), but its efficacy is frequently limited by tumor-intrinsic radioresistance. Cellular stiffness and extracellular matrix (ECM) interactions are critical mechanisms underlying this resistance. The adaptor protein four-and-a-half LIM domains 2 (FHL2) has emerged as a key regulator of tumor radioresistance. This study elucidates the role of FHL2 in enhancing radioresistance in NSCLC through ECM remodeling and cellular stiffness. FHL2 was found to promote cell survival, DNA damage repair, and ECM remodeling in response to irradiation, with its interaction with integrin β1 (ITGB1) playing a pivotal role. Depletion of FHL2 significantly reduced cell survival and radioresistance in radioresistant NSCLC cell lines, while FHL2 overexpression upregulated ITGB1 expression. Notably, FHL2 depletion elicited effects comparable to ITGB1 knockdown, suggesting ITGB1 acts as a downstream effector of FHL2. Mechanistically, FHL2 enhances ITGB1-mediated ECM remodeling and cellular stiffness via FAK/MAPK signaling pathways, thereby promoting radioresistance. These findings position FHL2 as a potential biomarker and therapeutic target for overcoming radioresistance in NSCLC, offering a foundation for developing strategies to improve radiotherapy outcomes. This study underscores the critical role of FHL2/ITGB1 axis in tumor resistance mechanisms and highlights its therapeutic potential in NSCLC treatment.

BackgroundN6-methyladenosine (m6A) modification is implicated in various diseases pathogenesis and physiological processes. We investigated the regulatory function of METTL3, a central m6A methyltransferase, in mediating m6A modification of YY1. This study aims to delineate how m6A modification of YY1 governs the pathogenesis of radiation-induced lung fibroblast injury and to elucidate its underlying molecular mechanism.MethodsThe expression of METTL3 and YY1 were quantified in human lung fibroblasts and Radiation-Induced Lung Injury (RILI) mouse models. We systematically investigated whether METTL3 regulates YY1 expression through m6A-dependent mechanisms and further assessed the involvement of IGF2BP1 in modulating YY1 mRNA stability.ResultsMETTL3 was significantly upregulated at both transcriptional and translational levels in RILI mouse lungs and irradiated human lung fibroblasts. YY1 expression was mechanistically depended on METTL3-mediated m6A modification. METTL3 depletion attenuated RILI progression, whereas YY1 overexpression partially ameliorated this phenotype. Crucially, IGF2BP1 directly interacts with m6A-modified YY1 mRNA to influence their expression and stability.ConclusionOur data show that METTL3-mediated m6A modification of YY1 plays a crucial role in RILI pathogenesis, and IGF2BP1 serves as an essential mediator for the stability of YY1 mRNA.

Neuropilin-1 (NRP1) is a transmembrane protein with diverse functions in tumor biology and immune system regulation. Despite extensive research, its specific function in radiation-induced lung injury (RILI) remains unclear. In this study, we aimed to explore the influence of NRP1 on immune and inflammatory responses mediated by regulatory T cells (Tregs) in RILI. Initial findings revealed that radiation increases the number of NRP1-expressing Tregs, which correlated with RILI severity. Inhibiting Tregs in mice effectively suppressed radiation-induced Treg differentiation and promoted helper T cell 1 (Th1) and Th2 cytokine expression, thereby shifting T cell polarization toward a Th1 phenotype and slowing RILI progression. However, Treg inhibition alone did not entirely prevent RILI, as skin damage and inflammatory factor expression persisted. Subsequent specific NRP1 knockdown in alveolar epithelial cell-II altered the inflammatory gene network, suppressed TGF-β signaling, reduced Treg levels, decreased IL-17 A and INF-γ expression, and shifted Th cell polarization toward Th2, alleviating RILI. In conclusion, this study reveals a novel mechanism by which NRP1 regulates immune and inflammatory responses in RILI, offering a promising avenue for developing innovative therapeutic strategies.

Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive lung disorder. Its pathological process involves persistent epithelial damage, ongoing inflammation, and dysregulated tissue repair. Currently, there are no effective treatment methods to improve patient survival. However, post-translational modifications (PTMs) have gradually garnered widespread attention. They are the processes by which various chemical groups are added to or removed from proteins' amino acid side chains or the N- or C-terminal ends of the polypeptide chain following synthesis. Additionally, they can regulate the energy supply of cells, regulate the cell cycle, and affect important signaling pathways such as TGF-β. This review systematically summarizes different categories of PTMs, organizes the PTMs involved in various injury stages of IPF, outlines the roles of different cells throughout the process, and analyzes future clinical diagnosis and treatment strategies as well as intervention targets for IPF, providing guiding significance for the systematic intervention of IPF in the future.

Radiation therapy has been a critical and effective treatment for cancer. However, not all cells are destroyed by radiation due to the presence of tumor cell radioresistance. In the current study, we investigated the effect of low-dose radiation (LDR) on the tumor suppressive effect of high-dose radiation (HDR) and its mechanism from the perspective of tumor cell death mode and DNA damage repair, aiming to provide a foundation for improving the efficacy of clinical tumor radiotherapy. We found that LDR pre-irradiation strengthened the HDR-inhibited A549 cell proliferation, HDR-induced apoptosis, and G2 phase cell cycle arrest under co-culture conditions. RNA-sequencing showed that differentially expressed genes after irradiation contained pyroptosis-related genes and DNA damage repair related genes. By detecting pyroptosis-related proteins, we found that LDR could enhance HDR-induced pyroptosis. Furthermore, under co-culture conditions, LDR pre-irradiation enhances the HDR-induced DNA damage and further suppresses the DNA damage-repairing process, which eventually leads to cell death. Lastly, we established a tumor-bearing mouse model and further demonstrated that LDR local pre-irradiation could enhance the cancer suppressive effect of HDR. To summarize, our study proved that LDR pre-irradiation enhances the tumor-killing function of HDR when cancer cells and immune cells were coexisting.

Insufficient reactive oxygen species (ROS) production and radioresistance have consistently contributed to the failure of radiotherapy (RT). The development of a biomaterial capable of activating ROS-induced apoptosis and ferroptosis is a potential strategy to enhance RT sensitivity. To achieve precision and high-efficiency RT, the theranostic nanoplatform Au/Cu nanodots (Au/CuNDs) were designed for dual-mode imaging, amplifying ROS generation, and inducing apoptosis-ferroptosis to sensitize RT. A large amount of ROS is derived from three aspects: (1) When exposed to ionizing radiation, Au/CuNDs effectively absorb photons and emit various electrons, which can interact with water to produce ROS. (2) Au/CuNDs act as a catalase-like to produce abundant ROS through Fenton reaction with hydrogen peroxide overexpressed of tumor cells. (3) Au/CuNDs deplete overexpressed glutathione, which causes the accumulation of ROS. Large amounts of ROS and ionizing radiation further lead to apoptosis by increasing DNA damage, and ferroptosis by enhancing lipid peroxidation, significantly improving the therapeutic efficiency of RT. Furthermore, Au/CuNDs serve as an excellent nanoprobe for high-resolution near-infrared fluorescence imaging and computed tomography of tumors. The promising dual-mode imaging performance shows their potential application in clinical cancer detection and imaging-guided precision RT, minimizing damage to adjacent normal tissues during RT. In summary, our developed theranostic nanoplatform integrates dual-mode imaging and sensitizes RT via ROS-activated apoptosis-ferroptosis, offering a promising prospect for clinical cancer diagnosis and treatment.

Radiation-Induced Pulmonary Fibrosis (RIPF) frequently arises as a delayed complication following radiation therapy for thoracic cancers, encompassing lung, breast, and esophageal malignancies. Characterized by a relentless and irreversible accumulation of extracellular matrix (ECM) proteins within the lung parenchyma, RIPF presents a significant clinical challenge. While the modulation of gene expression by transcription factors is a recognized aspect in various pathologies, their specific role in the context of RIPF has been less clear. This study elucidates that ionizing radiation prompts the translocation of the transcription factor GATA3 into the nucleus. This translocation facilitates GATA3's binding to the NRP1 promoter, thereby enhancing the transcription and subsequent translation of NRP1. Further investigations demonstrate that the TGF-β pathway agonist, SRI-011381, can mitigate the effects of NRP1 knockdown on epithelial-mesenchymal transition (EMT) and ECM deposition, suggesting a pivotal role of the GATA3/NRP1/TGF-β axis in the pathogenesis of RIPF. In conclusion, our findings not only underscore the critical involvement of GATA3 in RIPF but also highlight the GATA3/NRP1/TGF-β signaling pathway as a promising target for therapeutic intervention in RIPF management.

The tumor microenvironment (TME) is a complex and dynamic ecosystem composed of tumor cells, immune cells, supporting cells, and the extracellular matrix. Typically, the TME is characterized by an immunosuppressive state. To meet the demands of rapid proliferation, cancer cells undergo metabolic reprogramming, which enhances their biosynthesis and bioenergy supply. Immune cells require similar nutrients for activation and proliferation, leading to competition and immunosuppression within the TME. Additionally, tumor metabolites inhibit immune cell activation and function. Consequently, an immunosuppressed and immune-tolerant TME promotes cancer cell proliferation and metastasis. Long non-coding RNAs (lncRNAs), a category of non-coding RNA longer than 200 nucleotides, regulate tumor metabolic reprogramming by interacting with key enzymes, transporters, and related signaling pathways involved in tumor metabolism. Furthermore, lncRNAs can interact with both cellular and non-cellular components in the TME, thereby facilitating tumor growth, metastasis, drug resistance, and inducing immunosuppression. Recent studies have demonstrated that lncRNAs play a crucial role in reshaping the TME by regulating tumor metabolic reprogramming. In this discussion, we explore the potential mechanisms through which lncRNAs regulate tumor metabolic reprogramming to remodel the TME. Additionally, we examine the prospects of lncRNAs as targets for anti-tumor therapy and as biomarkers for tumor prognosis.

BACKGROUND:Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.METHODS:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry.RESULTS:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion.CONCLUSIONS:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

Insufficient accumulation of reactive oxygen species (ROS) due to tumor hypoxia significantly contributes to increased radiation resistance and the failure of radiotherapy (RT). Therefore, developing methods to alleviate hypoxia and boost ROS levels represents a promising strategy for enhanced radiosensitivity. This study introduced a self-cascade catalytic Pt@Au nanozymes as a radiosensitizer, using glucose oxidase (GOx)-, catalase (CAT)-, and peroxidase (POD)-like activities to improve hypoxia and increase ROS accumulation, thereby affecting glucose metabolism and enhancing the effects of RT. Pt@Au nanozymes exhibit GOx-like activity, which not only depletes glucose to induce starvation therapy, but also generates hydrogen peroxide (H2O2) for cascade reactions. Moreover, Pt@Au nanozymes demonstrate CAT-like activity, catalyzing the conversion of H2O2 to O2. This conversion effectively alleviates hypoxia, stabilizes ROS, increases DNA damage, significantly enhancing RT efficacy and sustaining the effects of starvation therapy. As high-Z materials, Pt@Au nanozymes can deposit more X-ray energy. Furthermore, the POD-like activity catalyzes the conversion of H2O2 into highly reactive hydroxyl radicals (·OH), which increases ROS levels and enhances RT. Pt@Au nanozymes serve as X-ray computed tomography (CT) imaging agents, allowing for clear differentiation between tumor and normal tissue boundaries and enhancing the precision of RT. In summary, Pt@Au nanozymes serve as effective radiosensitizers by depleting glucose to induce starvation therapy, enhancing cascade reactions, and inhibiting tumor proliferation. Through their self-cascade reactions, these nanozymes dramatically increase oxygen levels within tumors, reduce hypoxia, and enhance ROS levels. This advancement addresses the radioresistance associated with hypoxic tumors, paving the way for innovative strategies in RT.

Radiotherapy (RT) is one of the most widely used treatment strategies for cervical cancer. However, radiation resistance poses a significant challenge in clinical practice, leading to poor prognosis and cancer-related deaths following RT. Herein, the multifunctional bimetallic nanoplatform Au/Fe nanodots (Au/FeNDs) were constructed to serve as an excellent radiosensitizer and reverse radiation resistance, aiming to enhance the therapeutic efficiency of RT. Au/FeNDs can generate a sufficient amount of reactive oxygen species through the Fenton reaction, thus achieving chemodynamic therapy (CDT). This in turn facilitates the damage of biomacromolecules such as DNA and lipids, promoting oxidative damage and inducing ferroptosis of tumor cells. Further, Au/FeNDs can also deposit more X-ray energy, increase DNA damage, and induce cell cycle arrest in the radiosensitive G2/M phase, thus achieving RT-CDT-ferroptosis trifunctional synergistic therapy to enhance RT efficiency. In addition, Au/FeNDs display remarkable performance as a contrast agent for computed tomography, which can be used to differentiate the boundary between tumors and normal tissues, facilitating precise RT of tumors. In conclusion, the developed nanodots have the potential to overcome radiation resistance through their ability to induce oxidative damage and ferroptosis, suggesting their potential translational value in clinical applications.

Despite the importance of radiation therapy as a non-surgical treatment for non-small cell lung cancer (NSCLC), radiation resistance has always been a concern, due to poor patient response and prognosis. Therefore, it is crucial to uncover novel targets to enhance radiotherapy and investigate the mechanisms underlying radiation resistance. Previously, we demonstrated that NRP1 was connected to radiation resistance in NSCLC cells. In the present study, bioinformatics analysis of constructed radiation-resistant A549 and H1299 cell models revealed that transcription coactivator YAP is a significant factor in cell proliferation and metastasis. However, there has been no evidence linking YAP and NRP1 to date. In this research, we have observed that YAP contributes to radiation resistance in NSCLC cells by stimulating cell proliferation, migration, and invasion. Mechanistically, YAP dephosphorylation after NSCLC cell radiation. YAP acts as a transcription co-activator by binding to the transcription factor TEAD4, facilitating TEAD4 to bind to the NRP1 promoter region and thereby increasing NRP1 expression. NRP1 has been identified as a new target gene for YAP/TEAD4. Notably, when inhibiting YAP binds to TEAD4, it inhibits NRP1 expression, and Rescue experiments show that YAP/TEAD4 influences NRP1 to regulate cell proliferation, metastasis and leading to radiation resistance generation. According to these results, YAP/TEAD4/NRP1 is a significant mechanism for radioresistance and can be utilized as a target for enhancing radiotherapy efficacy.

BACKGROUND:Cervical cancer, encompassing squamous cell carcinoma and endocervical adenocarcinoma (CESC), presents a considerable risk to the well-being of women. Recent studies have reported that squalene epoxidase (SQLE) is overexpressed in several cancers, which contributes to cancer development. METHODS:RNA sequencing data for SQLE were obtained from The Cancer Genome Atlas. In vitro experiments, including colorimetry, colony formation, Transwell, RT-qPCR, and Western blotting were performed. Furthermore, a transplanted CESC nude mouse model was constructed to validate the tumorigenic activity of SQLE in vivo. Associations among the SQLE expression profiles, differentially expressed genes (DEGs), immune infiltration, and chemosensitivity were examined. The prognostic value of genetic changes and DNA methylation in SQLE were also assessed. RESULTS:SQLE mRNA expression was significantly increased in CESC. ROC analysis revealed the strong diagnostic ability of SQLE toward CESC. Patients with high SQLE expression experienced shorter overall survival. The promotional effects of SQLE on cancer cell proliferation, metastasis, cholesterol synthesis, and EMT were emphasized. DEGs functional enrichment analysis revealed the signaling pathways and biological processes. Notably, a connection existed between the SQLE expression and the presence of immune cells as well as the activation of immune checkpoints. Increased SQLE expressions exhibited increased chemotherapeutic responses. SQLE methylation status was significantly associated with CESC prognosis. CONCLUSION:SQLE significantly affects CESC prognosis, malignant behavior, cholesterol synthesis, EMT, and immune infiltration; thereby offering diagnostic and indicator roles in CESC. Thus, SQLE can be a novel therapeutic target in CESC treatment.