Lung cancer recurrence, particularly in NSCLC, remains a major challenge, with 30-70% of patients relapsing post-treatment. Traditional predictors like TNM staging and histopathology fail to account for tumor heterogeneity and immune dynamics. This review evaluates AI models integrating gene biomarkers (TP53, KRAS, FOXP3, PD-L1, and CD8) to enhance the recurrence prediction and improve the personalized risk stratification.

Following the PRISMA guidelines, we systematically reviewed AI-driven recurrence prediction models for lung cancer, focusing on genomic biomarkers. Studies were selected based on predefined criteria, emphasizing AI/ML approaches integrating gene expression, radiomics, and clinical data. Data extraction covered the study design, AI algorithms (e.g., neural networks, SVM, and gradient boosting), performance metrics (AUC and sensitivity), and clinical applicability. Two reviewers independently screened and assessed studies to ensure accuracy and minimize bias.

A literature analysis of 18 studies (2019-2024) from 14 countries, covering 4861 NSCLC and small cell lung cancer patients, showed that AI models outperformed conventional methods. AI achieved AUCs of 0.73-0.92 compared to 0.61 for TNM staging. Multi-modal approaches integrating gene expression (PDIA3 and MYH11), radiomics, and clinical data improved accuracy, with SVM-based models reaching a 92% AUC. Key predictors included immune-related signatures (e.g., tumor-infiltrating NK cells and PD-L1 expression) and pathway alterations (NF-κB and JAK-STAT). However, small cohorts (41-1348 patients), data heterogeneity, and limited external validation remained challenges.

AI-driven models hold potential for recurrence prediction and guiding adjuvant therapies in high-risk NSCLC patients. Expanding multi-institutional datasets, standardizing validation, and improving clinical integration are crucial for real-world adoption. Optimizing biomarker panels and using AI trustworthily and ethically could enhance precision oncology, enabling early, tailored interventions to reduce mortality.

Breast cancer (BC) has become the most common malignant tumor in women worldwide. This study was carried out to find and validate a novel molecular therapeutic target for BC.

Long non-coding RNA (lncRNA) AK023507 was selected as the study objects through microarray analysis. The function of lncRNA AK023507 was verified by various cell function experiments in vitro, subcutaneous tumorigenesis experiments, and lung metastasis model experiments in vivo. The RNA pull-down experiment and Western blot experiment were used to confirm the mechanism regulation pathway and the recovery experiment was used to verify it. TCGA datasets were used for clinical and immune function prediction analysis.

In vitro cell function tests and in vivo experiments suggested that overexpression of lncRNA AK023507 inhibited the proliferation and metastasis of BC cells. The RNA pull-down experiment and Western blot analysis validated that lncRNA AK023507 interacted with the dedicator of cytokinesis 4 (DOCK4) protein. Analysis of public databases predicted that DOCK4 is a potential prognostic risk factor associated with epithelial-mesenchymal transition (EMT) and central memory T cell (TCM) cellular immune infiltration.

LncRNA AK023507 inhibits the proliferation and metastasis of BC by regulating the DOCK4/β-catenin axis. This discovery will provide new potential therapeutic targets for BC.

Fibronectin extra domain B (FN‑EDB) is a unique domain of FN), whose expression is significantly upregulated in the tumor microenvironment (TME). FN‑EDB plays a key role in tumor cell adhesion, angiogenesis and invasion, and is closely related to tumor malignancy and poor prognosis. Moreover, the high expression of FN‑EDB in multiple cancer types makes it a potential therapeutic target. However, comprehensive studies of the mechanism of FN‑EDB in different cancer types and its potential as therapeutic targets are lacking. The present study aimed to explore the general role of FN‑EDB in multiple types of cancer and to integrate the knowledge of cell biology, molecular biology and immunology, so as to give a comprehensive understanding of the role of FN‑EDB in TME. Furthermore, by focusing on the use of FN‑EDB in clinical diagnosis and treatment, the potential of targeting FN‑EDB as a diagnostic and therapeutic target was evaluated and the progress in clinical trials of these drugs was discussed. By searching web sites such as PubMed and web of science, various high‑quality studies including RNA sequencing, drug experiments, cell experiments, animal models, clinical randomized controlled experiments and large‑scale cohort studies were collected, with sufficient evidence to support a comprehensive evaluation of the function and potential application of FN‑EDB. The present study revealed the general role of FN‑EDB in multiple types of cancer and evaluated its potential as a diagnostic and therapeutic target. It also provided a basis for future development of more effective and precise cancer therapies.

The development and progression of nasopharyngeal carcinoma (NPC) involves intricate interactions between tumor cells and other surrounding cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play pivotal roles in the progression of NPC, but their interactions remain largely unexplored. In this study, we revealed that NPC promoted M2-like polarization of TAMs through enhanced synthesis and secretion of WNT2. These M2-type macrophages, in turn, significantly boosted the proliferation and metastasis of NPC. This vicious cycle perpetuated the malignant progression of NPC. Mechanistically, elevated m6A modification of WNT2 in NPC stabilized its mRNA and facilitated its protein expression, which is coordinately regulated by the m6A "eraser" ALKBH5 and the "reader" YTHDF1. NPC promoted M2-like polarization of macrophages by activating the FZD2/β-catenin signaling axis through paracrine WNT2. Furthermore, elevated WNT2 can also trigger the WNT/β-catenin signaling pathway in NPC cells through autocrine signaling, synergically contributing to NPC development. The research reveals that WNT2 is upregulated in an m6A modification-dependent manner and promotes M2-like macrophages polarization of TAMs and malignant progression of NPC. This discovery provides novel potential molecular markers and therapeutic targets for the diagnosis and treatment of NPC.

Lung cancer is a leading cause for cancer-related mortality across the globe. In the last decade, significant advancements have been made in the research of non-small cell lung cancer (NSCLC). However, new biotherapeutic drugs urgently need to be developed. This study investigated the regulating effect of hyperoside on NSCLC progression.

The colony formation assay and Cell Counting Kit-8 were used to detect cell proliferation. The Transwell assay was used to monitor cell migration. NSCLC growth in vivo was examined using a subcutaneous xenograft model. Proteomics, immunohistochemistry, and immunofluorescence analyses were used to detect anticancer regulatory mechanisms.

The results showed that hyperoside treatment inhibited cell migration, proliferation, and tumor growth in NSCLC in vivo and in vitro. Also, hyperoside treatment promoted apoptosis and cell cycle S-phase arrest. Proteomics, immunohistochemistry, and immunofluorescence detection also showed that hyperoside treatment promoted autophagy-related protein 13 (ATG13)-mediated autophagy, which further increased NSCLC apoptosis.

In summary, the findings illustrated that hyperoside treatment suppressed NSCLC progression by promotingATG13 expression and enhancing autophagy activation, finally promoting autophagy and apoptosis.

Regulatory T cells (Tregs) are critical for maintaining the stability of the immune system and facilitating tumor escape through various mechanisms. Resting T cells are involved in cell-mediated immunity and remain in a resting state until stimulated, while effector T cells promote immune responses. Here, we investigated the roles of two gene signatures, one for resting Tregs (FOXP3 and IL2RA) and another for effector Tregs (FOXP3, CTLA-4, CCR8 and TNFRSF9) in pan-cancer. Using data from The Cancer Genome Atlas (TCGA), The Cancer Proteome Atlas (TCPA) and Gene Expression Omnibus (GEO), we focused on the expression profile of the two signatures, the existence of single nucleotide variants (SNVs) and copy number variants (CNVs), methylation, infiltration of immune cells in the tumor and sensitivity to different drugs. Our analysis revealed that both signatures are differentially expressed across different cancer types, and correlate with patient survival. Furthermore, both types of Tregs influence important pathways in cancer development and progression, like apoptosis, epithelial-to-mesenchymal transition (EMT) and the DNA damage pathway. Moreover, a positive correlation was highlighted between the expression of gene markers in both resting and effector Tregs and immune cell infiltration in adrenocortical carcinoma, while mutations in both signatures correlated with enrichment of specific immune cells, mainly in skin melanoma and endometrial cancer. In addition, we reveal the existence of widespread CNVs and hypomethylation affecting both Treg signatures in most cancer types. Last, we identified a few correlations between the expression of CCR8 and TNFRSF9 and sensitivity to several drugs, including COL-3, Chlorambucil and GSK1070916, in pan-cancer. Overall, these findings highlight new evidence that both Treg signatures are crucial regulators of cancer progression, providing potential clinical outcomes for cancer therapy.

Epithelial ovarian cancer (EOC) genetics research has been focused on germline or somatic mutations independently. Emerging evidence suggests that the somatic mutational landscape can be shaped by the germline genetic background. In this study, we aim to unravel the role of somatic alterations within EOC germline susceptibility regions by incorporating functional annotations. We investigate somatic events, including mutational signatures, point mutations, copy number alterations, and transcription factor binding disruptions, within 33 EOC germline susceptibility regions. Our analysis identifies significant associations between candidate germline susceptibility genes and somatic mutational signatures known to be key risk factors for EOC, such as mismatch repair deficiency, age-related mutagenesis, and homologous recombination deficiency. In addition, we find somatic point mutations and copy number alterations are significantly enriched in histotype-specific active enhancers and promoters within EOC risk loci. Furthermore, we examine the impact of germline variants and somatic mutations on transcription factor binding sites, identifying cancer developmental transcription factor motifs frequently affected by both types of mutations. Overall, our study highlights the importance of integrating germline and somatic mutations with regulatory and epigenomic data to gain insights into the genetic basis of EOC.

Glioblastoma remains the most common and aggressive primary tumor of the central nervous system in adults. Current treatment options include standard surgical resection combined with radiation/chemotherapy, but such protocol most likely only delays the inevitable. Therefore, the problem of finding therapeutic targets to prevent the occurrence and development of this severe oncological disease is currently acute. It is known that the functions of selenoproteins in the regulation of carcinogenesis processes are not unambiguous. Either they exhibit cytotoxic activity on cancer cells, or cytoprotective. A special place in the progression of oncological diseases of various etiologies is occupied by proteins of the thioredoxin and glutathione systems. These are two cellular antioxidant systems that regulate redox homeostasis, counteracting the increased production of reactive oxygen species in cells. The review reflects the latest data on the role of key enzymes of these redox systems in the regulation of processes associated with the progression of glioblastoma. A thorough consideration of these issues will expand fundamental knowledge about the functions of selenium-containing thioredoxin reductases and glutathione peroxidases in the therapy of glioblastomas and provide an understanding of the prospects for the treatment of this aggressive oncological disease.

To study the pharmacological effects of solasonine (Sol) in inhibiting non-small cell lung cancer (NSCLC) metastasis.

The pharmacological effects of solasonine were examined in vitro by continuous induction of NSCLC cells by no treatment, or TGF-β, or creatine. Cell migration and invasion were assessed via wound healing and transwell assays, and the levels of epithelial-mesenchymal transition (EMT) markers were determined using immunofluorescence and Western Blot. Solasonine's ability to bind to TGF-β and creatine transferases and isoenzymes was assessed by TCGA, KMPLOT database, cellular thermal shift assay (CETSA), and molecular docking assay. In vivo, two types of NSCLC cells were injected into mice using the tail vein. Solasonine's effect on tumor metastasis was determined using in vivo fluorescent probes, hematoxylin-eosin staining assay, and immunofluorescence.

Unlike traditional therapies targeting TGF-β receptors, Sol was shown to inhibit NSCLC metastasis through a novel mechanism independent of TGF-β signaling. Creatine was found to promote NSCLC metastasis in vitro by enhancing cell migration, invasion, and EMT-related protein expression, and in vivo by increasing metastasis to the liver. These effects were mediated by the activation of Smad2 phosphorylation and EMT independently of TGF-β. Sol effectively counteracted these effects by targeting guanidinoacetate methyltransferase (GATM) with high binding affinity, thereby suppressing the TTK-mediated Smad2 pathway and significantly reducing metastasis to the lungs and liver, as confirmed by HE staining and fluorescence imaging.

This study identifies solasonine as a novel inhibitor of NSCLC metastasis, acting through the GATM and Smad2 pathways to counter creatine-induced metastasis. These findings underscore the potential of Sol as a therapeutic candidate for metastatic NSCLC.

Immunoscore (IS), based on CD3/CD8, has been proposed to characterize the immune landscape of the tumor immune microenvironment and has demonstrated an association with the prognosis of laryngeal squamous cell carcinoma (LSCC). However, traditional IS does not include immunosuppressive cells. The purpose of this study is to evaluate the prognostic performance of cytotoxic-T-lymphocytes to immunosuppressive cells ratio (CIL) in laryngeal squamous cell carcinoma (LSCC) patients. Two cohorts were included in this study: The training cohort (N = 75) consisted of tumor tissue microarrays from LSCC patients in our department, and the validation cohort (N = 116) utilized bulk RNA-seq data from the TCGA database. Patients with high IS or CIL showed significantly prolonged overall survival and disease-free survival in both cohorts. Upon analyzing the relative contribution of each parameter, it was found that CIL exhibited the highest significance among the factors examined. It emerged as the strongest predictor of overall survival, emphasizing its crucial influence in determining the outcomes. The prognostic ability of IS-TCGA was similar to the original IS. Additionally, high CILM2-TCGA was associated with prolonged survival of patients with LSCC in the TCGA dataset. CIL, which is easier to construct than IS, proves to be reliable in predicting survival outcomes for patients with LSCC.

Epithelial-mesenchymal transition (EMT) and circulating tumor cells (CTCs) are key prognostic factors in nasopharyngeal carcinoma (NPC). However, the role of EMT status in CTCs for predicting outcomes in advanced NPC treated with radiotherapy after induction chemotherapy remains unclear.

A total of 143 CTC tests from 95 advanced/metastatic NPC patients were analyzed before, during, and after radiotherapy, with a 60-month follow-up. CTC count, matrix metalloproteinase 2 (MMP2)) protein expression, and EMT subtypes were examined.

During radiotherapy, CTC counts increase but decrease afterward. Patients with higher pre-radiotherapy tumor-node-metastasis (TNM) stages have lower total and M-subtype CTC counts. Higher T and TNM stages during radiotherapy correlate with increased EMT-state CTCs, especially hybrid CTCs. EA/IgG-positive patients have a higher number of hybrid CTCs and E-type (epithelial + hybrid) CTCs, while EBV-EA-negative patients have more mesenchymal CTCs. A higher post-radiotherapy CTC count predicts relapse, and the positive rate of MMP2 expression on hybrid and epithelial CTCs is higher than that on mesenchymal CTCs.

EMT status, particularly in hybrid CTCs, is a potential prognostic marker for relapse in advanced NPC after radiotherapy.

Prostate cancer (PCa) remains a significant challenge in oncology due to high rates of drug resistance following standard treatment with docetaxel-based chemotherapy. Asporin (ASPN) has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. Studies indicated that abnormal activation of the Wnt/β-catenin signaling pathway is prevalent in PCa. This study investigated the important role of ASPN in regulating Wnt/β-catenin signaling pathway in docetaxel resistance and metastasis of PCa.

The impacts of ASPN on the docetaxel chemoresistance and metastasis of PCa cells were investigated in vitro and in vivo assays. Lastly, the underlying mechanism of ASPN was revealed by Western blot, protein immunocoprecipitation, Immunofluorescence, Immunohistochemical staining, liquid chromatography-mass spectrometry, and rescue experiments.

In present study, we reported that ASPN is highly expressed in PCa cells and tissues. Functional and molecular analyses showed that ASPN is activated by TGFβ and interacts with STMN1. ASPN increases the expression of β-catenin and promotes its nuclear accumulation by mediating the activation of the Wnt/β-catenin signaling pathway, thereby enhancing the stemness and epithelial-mesenchymal transition (EMT) of PCa cells, ultimately facilitating the docetaxel resistance and metastasis of PCa cells.

Our findings identify ASPN as a novel upstream regulatory factor of Wnt/β-catenin signaling pathway, suggesting that targeting the ASPN/STMN1/β-catenin axis could be a promising strategy for PCa intervention.

Cancer stemness plays a crucial role in promoting the progression of colorectal cancer (CRC). Forkhead box N3 (FOXN3) is a tumor suppressor protein. Herein, we investigated the role of FOXN3 in the regulation of CRC cell stemness. Cell viability, proliferation, migration, and invasion were assessed utilizing cell counting kit-8 assay, 5-ethynyl-20-deoxyuridine assay, and Transwell assay, respectively. Cell-sphere formation was assessed using a sphere-forming assay. The enrichment of H3K27ac modifications at the SRY-related HMG-box 12 (SOX12) promoter, interactions among FOXN3, SOX12, and E1A binding protein p300 (EP300) were analyzed using chromatin immunoprecipitation or dual luciferase reporter assays. We found that FOXN3 overexpression inhibited CRC cell proliferation, migration, invasion, stemness, and tumor formation in mice by inactivating the Wnt/β-catenin signaling, while these effects of FOXN3 overexpression were reversed by the overexpression of SOX12. Mechanistically, EP300 increased SOX12 expression in CRC cells by promoting H3K27ac enrichment in the SOX12 promoter. In addition, FOXN3 transcriptionally inhibited EP300 expression in CRC cells by binding to the EP300 promoter. As expected, EP300 overexpression weakened the inhibitory effect of FOXN3 overexpression on CRC cell stemness. Collectively, FOXN3 upregulation inhibited CRC cell stemness by suppressing EP300-mediated epigenetic upregulation of SOX12.

Liver metastasis is a leading cause of mortality from malignant tumors and significantly impairs the efficacy of therapeutic interventions. In recent years, both preclinical and clinical research have made significant progress in understanding the molecular mechanisms and therapeutic strategies of liver metastasis. Metastatic tumor cells from different primary sites undergo highly similar biological processes, ultimately achieving ectopic colonization and growth in the liver. In this review, we begin by introducing the inherent metastatic-friendly features of the liver. We then explore the panorama of liver metastasis and conclude the three continuous, yet distinct phases based on the liver's response to metastasis. This includes metastatic sensing stage, metastatic stress stage, and metastasis support stage. We discuss the intricate interactions between metastatic tumor cells and various resident and recruited cells. In addition, we emphasize the critical role of spatial remodeling of immune cells in liver metastasis. Finally, we review the recent advancements and the challenges faced in the clinical management of liver metastasis. Future precise antimetastatic treatments should fully consider individual heterogeneity and implement different targeted interventions based on stages of liver metastasis.

Despite significant advances in targeted therapies and immunotherapies, non-small cell lung cancer (NSCLC) continues to present a global health challenge, with a modest five-year survival rate of 28 %, largely due to the emergence of treatment-resistant and metastatic tumors. In response, we synthesized a novel bioactive compound, ethyl 6-chlorocoumarin-3-carboxylyl L-theanine (TClC), which significantly inhibited NSCLC growth, epithelial mesenchymal transition (EMT), migration, and invasion in vitro and tumor growth and metastasis in vivo without inducing toxicity. TClC disrupts autocrine loops that promote tumor progression, particularly in stem-like CD133-positive NSCLC (CD133+ LC) cells, which are pivotal in tumor metastasis. Through targeted molecular assays, we identified direct binding targets of TClC, including Akt, NF-κB, β-catenin, EZH2, and PD-L1. This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter, underscoring the compound's polypharmacological potential. These results position TClC as a promising candidate for NSCLC treatment, signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways.

Lung cancer is a highly prevalent and deadly disease worldwide, causing over 1.2 million deaths each year. Pingxiao Pian (PXP) tablets, a Chinese traditional medicine, have been widely applied in the treatment of lung cancer. However, the mechanism underlying therapeutic effects of PXP tablets remains undisclosed.

A549 human LUAD cell line was utilized for in vitro experiments. Transfection of miR-29b mimic was performed using Lipofectamine 3000. PXP was purchased and dissolved into PBS and drinking water after carefully removing the outer coating. Dual-luciferase reporter assay was conducted to assess the regulatory effect of miR-29b on TGF-β1. The protein levels of epithelial-mesenchymal transition (EMT) markers and activation of TGF-β1 pathway were characterized using immunoblotting analysis.

PXP reduced the invasiveness and proliferation of LUAD cells by increasing miR-29b-3p expression in vitro. Overexpression of miR-29b-3p resulted in decreased cell proliferation and invasiveness, while silencing of miR-29b-3p in the A549 cells displayed the opposite effect. Moreover, PXP treatment reversed the increased cell proliferating rate triggered by miR-29b-3p silencing. Additionally, PXP was found to hamper EMT occurrence in A549 cells by regulating miR-29b-3p and reduce expression of N-cad and vimentin. Overexpression of miR-29b-3p blocked the phosphorylation of Smad2/3 and decreased TGF-β1 expression. Luciferase assay results indicated that miR-29b-3p directly regulated TGF-β1 expression. In vivo tumor formation experiments confirmed the tumor-reducing effects of PXP and the role of miR-29b in tumor progression. PXP treatment decreased tumor size and weight via regulating miR-29b-3p.

Our study suggests that PXP exerts anti-tumor effects in LUAD through the regulation of miR-29b and the inhibition of EMT via the TGF-β1/Smad2/3 pathway.

This study aimed to investigate the regulatory effects of the long non-coding RNA (lncRNA) MISATO family member 2 (MSTO2P) on non-small cell lung cancer (NSCLC) cell viability, invasion, and migration, as well as the underlying mechanism. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression levels of MSTO2P. The effects of MSTO2P on cell viability, invasion, and migration were assessed using cell counting kit-8 (CCK-8), Transwell invasion, and wound healing assays in A549 and H1229 cells. A human phospho-kinase array kit was employed to identify potential phosphorylated kinases or signaling nodes affected by MSTO2P. The interaction between MSTO2P and β-catenin was evaluated using RNA pull-down and RNA immunoprecipitation (RIP) assays. A xenograft tumor mouse model was established to evaluate tumor growth. The results demonstrated that MSTO2P expression was elevated in NSCLC tissues and cells compared to normal counterparts. Silencing MSTO2P inhibited the viability, invasion, and migration of A549 and H1229 cells. MSTO2P interacted with β-catenin, thereby activating the Wnt/β-catenin pathway. Overexpression of MSTO2P or β-catenin promoted the viability, invasion, and migration of A549 and H1229 cells, effects that were reversed by treatment with XAV-939. In vivo studies showed that silencing MSTO2P suppressed tumor growth. In conclusion, MSTO2P promoted NSCLC cell viability, invasion, and migration by regulating the Wnt/β-catenin pathway, suggesting that MSTO2P may be a potential therapeutic target for NSCLC.

The invasion and metastasis of pancreatic cancer (PC) are key factors contributing to disease progression and poor prognosis. This process is primarily driven by EMT, which has been the focus of recent studies highlighting the role of long non-coding RNAs (lncRNAs) as crucial regulators of EMT. However, the mechanisms by which lncRNAs influence invasive metastasis are multifaceted, extending beyond EMT regulation alone.

This review primarily aims to characterize lncRNAs affecting invasion and metastasis in pancreatic cancer. We summarize the regulatory roles of lncRNAs across multiple molecular pathways and highlight their translational potential, considering the implications for clinical applications in diagnostics and therapeutics.

The review focuses on three principal scientific themes. First, we primarily summarize lncRNAs orchestrate various signaling pathways, such as TGF-β/Smad, Wnt/β-catenin, and Notch, to regulate molecular changes associated with EMT, thereby enhancing cellular motility and invasivenes. Second, we summarize the effects of lncRNAs on autophagy and ferroptosis and discuss the role of exosomal lncRNAs in the tumor microenvironment to regulate the behavior of neighboring cells and promote cancer cell invasion. Third, we emphasize the effects of RNA modifications (such as m6A and m5C methylation) on stabilizing lncRNAs and enhancing their capacity to mediate invasive metastasis in PC. Lastly, we discuss the translational potential of these findings, emphasizing the inherent challenges in using lncRNAs as clinical biomarkers and therapeutic targets, while proposing prospective research strategies.

Immunogenic cell death (ICD) can be triggered by various therapies to induce anti-tumor immune responses, significantly enhancing treatment effectiveness, and is widely utilized in tumor immunotherapy.

LUAD data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) validated ICD-related molecular subtypes via consensus clustering. Clinical features, ICD genes, driver genes, mutations, tumor microenvironment, immune checkpoints, and drug sensitivity were compared. RT-qPCR, Western blot, immunofluorescence, ELISA, flow cytometry, and tube formation assays validated findings.

Differential expression of 33 ICD genes was observed between tumor and normal tissues. These genes were clustered into two groups via consensus clustering and validated with GEO data. Prognostic analysis indicated superior outcomes in cluster 2 across TCGA and GEO cohorts. Significant disparities in clinicopathological characteristics like stage, gender, and age were noted between subtypes. Cluster 2 exhibited heightened expression of ICD-related genes, driver genes, immune checkpoints, and immune cells. Cluster 2 also showed increased sensitivity to chemotherapy drugs. IFNG overexpression in A549 and H1299 cells induced CRT exposure, HMGB1 release, and ATP secretion, thereby promoting dendritic cell maturation and enhancing CD8+ T cell function. Additionally, IFNG boosted tumor angiogenesis via HMGB1 pathways, which could be mitigated by HMGB1 inhibition.

Identification of novel ICD-related molecular subtypes holds promise for guiding personalized therapies, assessing prognosis, and predicting immunotherapy efficacy in LUAD. IFNG emerges as a potential prognostic biomarker and therapeutic target, influencing both the tumor microenvironment and angiogenesis. These findings offer new insights into therapeutic strategies targeting IFNG-mediated pathways in LUAD.

Clear cell renal cell carcinoma (ccRCC) remains a challenging cancer type due to its resistance to standard treatments. Immunogenic cell death (ICD) has the potential to activate anti-tumor immunity, presenting a promising avenue for ccRCC therapies.

We analyzed data from GSE29609, TCGA-KIRC, and GSE159115 to identify ICD-related prognostic genes in ccRCC. By applying consensus clustering, patients were categorized based on ICD modification patterns, and an ICD signature (ICDS) model was developed using a PCA approach. Functional studies were conducted with FOXP3 knockdown in ccRCC cell lines to explore its impact on cell behavior.

Eleven ICD-related genes were identified as key prognostic indicators in ccRCC, with high ICDS linked to worse survival outcomes. High ICDS also correlated with increased levels of immune-suppressive cells within the tumor microenvironment. FOXP3 was highlighted as a critical gene influencing ICD, where its knockdown significantly reduced ccRCC cell proliferation and migration, underscoring its role in tumor progression.

This study establishes FOXP3 as a pivotal factor in ICD regulation and ccRCC progression. Targeting FOXP3 and other ICD pathways could enhance treatment efficacy in ccRCC, providing a foundation for ICD-based therapeutic strategies. Evaluating ICD patterns in ccRCC may guide patient-specific interventions, paving the way for improved management of this aggressive cancer.

Inorganic arsenic is a Class I human Carcinogen. However, the role of chronic inorganic arsenic exposure on prostate cancer metastasis still unclear. This study aimed to investigate the effects and mechanism of chronic NaAsO2 exposure on migration and invasion of prostate cancer cells. DU145 and PC-3 cells were exposed to NaAsO2 (2 μM) for 25 generations. Wound healing and Transwell assays showed that chronic NaAsO2 exposure promoted migration and invasion of DU145 and PC-3 cells. In addition, chronic NaAsO2 exposure induced epithelial-mesenchymal transition (EMT) of DU145 cells by promoting β-catenin/TCF4 transcriptional activity. Mechanically, NaAsO2 promoted GSK-3β inactivation in the "disruption complex" through Akt- mediated phosphorylation at serine 9, and then inhibited the phosphorylation and ubiquitination degradation of β-catenin, which led to its nuclear translocation. Ly294002, a selective phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, suppressed the β-catenin/TCF4 complex activation and EMT through blocking Akt-mediated GSK-3β inactivation in the "disruption complex" in chronic NaAsO2 exposed DU145 and PC-3 cells. Moreover, Ly294002 alleviated chronic NaAsO2-induced migration and invasion in DU145 and PC-3 cells. These findings provide evidence that chronic arsenic exposure promotes migration and invasion of prostate cancer cells via an EMT mechanism driven by the AKT/GSK-3β/β-catenin/TCF4 signaling axis. Akt is expected to be a potential therapeutic target for chronic arsenic exposure-mediated prostate cancer metastasis.

Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/β-catenin pathway associated proteins (β-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/β-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/β-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/β-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.

The underlying mechanisms between cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) remain unclear. In this study, we identified TGIF2 as a target gene of CSC using sncRNA and machine learning. TGIF2 is closely related to the expression of SOX2, EGFR, and E-cadherin, indicating poor prognosis. Mechanistically, TGIF2 promoted the EMT phenotype and CSC properties following the activation of SOX2, Slug, CD44, and ERGF/MAPK signaling, which were rescued by SOX2 silencing. TGIF2 silencing contributes to the opposite phenotype via SOX2. Notably, Smad2 cooperates with TGIF2 to co-regulate the SOX2 promoter, which in turn promotes EMT and CSC signaling by transactivating Slug and EGFR, respectively. The transactivation of EGFR/MAPK signaling by SOX2 promotes TGIF2 nuclear translocation, forming a positive feedback loop in vitro. Moreover, the interaction of TGIF2 and SOX2 with EGFR inhibitors promoted subcutaneous tumors and liver metastasis in vivo. Thus, the TGIF2/SOX2 axis contributes to CSC, EMT, and chemoresistance, providing a promising target for PC therapy.

To better understand cervical cancer progression, we analyzed RNA from 262 biopsies from women referred for colposcopy. We determined the HPV type and analyzed the expression of 51 genes. HPV31 was significantly more prevalent in precancer than stage 1 cancer and invasive cancer (p < 0.0001), and HPV16 increased in invasive disease (p < 0.0001). CCNE1, MELTF, and ULBP2 were significantly increased in HPV16-positive compared to HPV31 precancers, while NECTIN2 and HLA-E expression decreased. Markers of the innate immune system, DNA repair genes, and cell cycle genes are significantly increased during cancer progression (p = 0.0001). In contrast, the TP53 and RB1 tumor suppressor gene expression is significantly decreased in cancer cells. The T cell markers CD28 and FLT3LG expression decreased in cancer while FOXP3, IDO1, and ULBP2 expression increased. There is a significantly higher survival rate in individuals with increased expression of CD28 (p = 0.0005), FOXP3 (p = 0.0002), IDO1 (p = 0.038), FLT3LG (p = 0.026), APOBEC3B (p = 0.0011), and RUNX3 (p = 0.019), and a significantly lower survival rate in individuals with increased expression of ULBP2 (p = 0.035). These results will help us elucidate the molecular factors influencing the progression of cervical precancer to cancer. Understanding the risk of progression of specific HPV types and sublineages may aid in the triage of positive patients, and better knowledge of the immune response may aid in developing and applying immunotherapies.

CD40 agonist antibodies (αCD40) have shown promising anti-tumor response in both preclinical and early clinical studies. However, its systemic administration is associated with immune- and hepato-toxicities which hampers its clinical usage. In addition, αCD40 showed low tumor retention and induced PD-L1 expression which makes tumor microenvironment (TME) immunosuppressive. To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it. Immunosomes showed higher tumor accumulation till 96 h of administration and displayed sustained release of αCD40 in vivo. Immunosomes significantly delayed tumor growth and showed tumor free survival in mice bearing GL-261 glioblastoma by increasing the population of CD45+CD8+ T cells, CD45+CD20+ B cells, CD45+CD11c+ DCs and F4/80+CD86+ cells in TME. Immunosome significantly reduced the population of T-regulatory cells, M2 macrophage, and MDSCs and lowered the PD-L1 expression. Moreover, Immunosomes significantly enhanced the levels of Th1 cytokines (IFN-γ, IL-6, IL-2) over Th2 cytokines (IL-4 and IL-10) which supported anti-tumor response. Most interestingly, Immunosomes averted the in vivo toxicities associated with free αCD40 by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-1α and reduced the degree of liver damage. In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.

Information on the potential role of the long non-coding RNA LNC-POTEM-4 in cancer progression is limited. Our preliminary study found that LNC-POTEM-4 was overexpressed in hepatocellular carcinoma (HCC) tissues, which led us to further investigate the biological function and molecular mechanism of LNC-POTEM-4 in HCC development. LNC-POTEM-4 expression in HCC tissues was examined using transcriptome sequencing and quantitative reverse transcription PCR. The relationships between LNC-POTEM-4 and the stage and prognosis of HCC in patient data from the TCGA database were analyzed. The effects of LNC-POTEM-4 on proliferation, invasion/migration, and epithelial-mesenchymal transition marker expression in HCC cells were evaluated in vitro using gain- and loss-of-function assays, while its effects on tumor growth and metastasis were explored through animal experiments. A LNC-POTEM-4/microRNA (miR)-149-5p/Wnt4 regulatory signaling axis was identified using bioinformatics analysis, and dual luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Co-transfection of LNC-POTEM-4 and Wnt4 expression plasmids was employed to confirm the new signaling pathway. We found that LNC-POTEM-4 was overexpressed in HCC tissues and was linked to poor staging and prognosis. LNC-POTEM-4 promoted proliferation, invasion, migration, and the epithelial-mesenchymal transition of HCC cells in vitro. Silencing of LNC-POTEM-4 inhibited HCC growth and distant metastasis in vivo. Mechanically, LNC-POTEM-4 was found to function as a competitive endogenous RNA, upregulating Wnt4 by sponging miR-149-5p to promote HCC progression. Wnt4 overexpression may have counteracted the tumor-inhibition effect of LNC-POTEM-4 silencing. In conclusion, LNC-POTEM-4 upregulated Wnt4 to activate the Wnt signaling pathway and stimulate the malignancy tendency of HCC by sponging miR-149-5p, providing a prospective target for the detection and therapy of HCC. However, the effects of LNC-POTEM-4 on the miR-149-5p/Wnt4 signaling axis should be further studied in animal experiments.

Hippo signalling is involved in the coordination of extracellular signals that control tissue homeostasis and organ size. Yes-associated protein 1 (YAP1) is regulated primarily by Hippo signalling through coactivation of transcription factors with GATA domains called TEADs. However, small-molecule orthosteric inhibitors of YAP1 are difficult to develop due to its tight binding to TEAD4 via a flat interface. Previous studies have shown that chlorpromazine (CPZ) can inhibit YAP1 expression. MTT, colony formation, wound healing, Transwell migration and Western blot assays were performed to explore how CPZ affects nasopharyngeal carcinoma (NPC) cells through FOXP3. In addition, immunofluorescence and live-cell imaging were used to detect YAP1 intracellular localization after CPZ administration. Through the HDOCK website, we predicted protein binding regions between FOXP3 and TEAD4. Western blot and co-IP experiments were used to verify the relationship between FOXP3 and YAP1. The UCSC Xena database, LinkedOmics database and KM plotter website were used to assess the prognostic value of FOXP3 in head and neck squamous cell carcinoma (HNSCC). Age, sex, pathological tumour-node-metastasis (pTMN) stage, grade, smoking status and FOXP3 expression were included in an overall survival nomogram model. Our findings revealed that FOXP3 has the ability to competitively interacts competitively with TEAD4 to inhibit YAP1 expression. By increasing FOXP3 expression, CPZ induces YAP1 nuclear export and phosphorylation, consequently suppressing NPC cell proliferation and migration. Collectively, our findings indicate that FOXP3 competitively binds TEAD4 to regulate YAP1 localization in the nucleus and cytoplasm to suppress NPC progression. Consequently, FOXP3 may be a prognostic indicator for HNSCC.

Emerging evidence highlights certain long noncoding RNAs (lncRNAs) transcribed from or interacting with super-enhancer (SE) regulatory elements. These lncRNAs, known as SE-lncRNAs, are strongly linked to cancer and regulate cancer progression through multiple interactions with downstream targets. The expression of SE-lncRNAs is controlled by various transcription factors (TFs), and dysregulation of these TFs can contribute to cancer development. In this review, we discuss the characteristics, classification and subcellular distribution of SE-lncRNAs and summarise the role of key TFs in the transcription and regulation of SE-lncRNAs. Moreover, we examine the distinct functions and potential mechanisms of SE-lncRNAs in cancer progression.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. This research focuses on investigating the impact and underlying molecular mechanisms of protocadherin gamma subfamily A, 9 (PCDHGA9) on the invasion and metastasis of CRC, aiming to identify more precise molecular markers for the diagnosis and prognosis of CRC.

PCDHGA9 expression was detected using quantitative real-time quantitative polymerase chain reaction (RT-qPCR) in 63 pairs of colorectal cancer tissues. Differential gene expression from high-throughput sequencing was analyzed using ingenuity pathway analysis (IPA) to explore the biological functions of PCDHGA9 and its potential regulated genes. Bioinformatics tools were employed to explore potential upstream regulatory microRNAs of PCDHGA9. Dual-luciferase assays were performed to demonstrate the regulation between PCDHGA9 and miR-1269a. Protein mass spectrometry suggested an interaction between PCDHGA9 and HOXA1. JASPAR predicted that HOXA1 may act as a transcription factor of CXCR4. Coimmunoprecipitation, dual-luciferase assays, and nuclear-cytoplasmic fractionation experiments confirmed the molecular mechanism involving PCDHGA9, CXCR4, HOXA1, and β-catenin. Transwell, wound healing, and western blot assays were conducted to confirm the impact of PCDHGA9, miR-1269a, and CXCR4 on the invasion, metastasis, and epithelial-mesenchymal transition (EMT) functions of CRC cells in in vitro experiments. A whole-body fluorescence imaging system was used to evaluate the combined impact of miR-1269a and PCDHGA9 on the invasion and metastasis of CRC in in vivo experiments.

The expression of PCDHGA9 was found to be lower in CRC tissues compared with their corresponding adjacent tissues. Low expression of PCDHGA9 potentially correlated with worse prognosis and increased chances of invasion and metastasis in CRC. miR-1269a was highly expressed in CRC tissues and acted as a negative regulator for PCDHGA9, promoting invasion, migration, and EMT of CRC cells. PCDHGA9's interaction with HOXA1 downregulated CXCR4, a transcription factor, leading to accumulation of β-catenin and further promoting invasion, migration, and EMT of CRC cells.

PCDHGA9, acting as a tumor suppressor, is downregulated by miR-1269a. The low level of PCDHGA9 activates the Wnt/β-catenin pathway by releasing its interaction with HOXA1, promoting the expression of CXCR4, and causing invasion, migration, and EMT in CRC.

Gastric cancer (GC) is a leading cause of cancer-related deaths globally, necessitating the identification of novel therapeutic targets. This study investigates the roles of MATN3 and ASPN in GC progression via the epithelial-mesenchymal transition (EMT) pathway. Analysis of the Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD) dataset revealed that both MATN3 and ASPN are significantly upregulated in GC tissues and correlate with poor patient survival. Protein-protein interaction and co-expression analyses confirmed a direct interaction between MATN3 and ASPN, suggesting their synergistic role in EMT activation. Functional assays demonstrated that MATN3 promotes GC cell proliferation, migration, and invasion, while its knockdown inhibits these malignant behaviors and induces apoptosis. ASPN overexpression further amplified these oncogenic effects. In vivo, studies in a mouse model corroborated that co-overexpression of MATN3 and ASPN enhances tumor growth and metastasis. These findings highlight the MATN3-ASPN axis as a potential therapeutic target in GC, offering new insights into the molecular mechanisms driving GC progression.

Co-infection with oncogenic retrovirus and herpesvirus significantly facilitates tumor metastasis in human and animals. Co-infection with avian leukosis virus subgroup J (ALV-J) and Marek's disease virus (MDV), which are typical oncogenic retrovirus and herpesvirus, respectively, leads to enhanced oncogenicity and accelerated tumor formation, resulting in increased mortality of affected chickens. Previously, we found that ALV-J and MDV cooperatively promoted tumor metastasis. However, the molecular mechanism remains elusive. Here, we found that doublecortin-like kinase 1 (DCLK1) mediated cooperative acceleration of epithelial-mesenchymal transition (EMT) by ALV-J and MDV promoted tumor metastasis. Mechanistically, DCLK1 induced EMT via activating Wnt/β-catenin pathway by interacting with β-catenin, thereby cooperatively promoting tumor metastasis. Initially, we screened and found that DCLK1 was a potential mediator for the cooperative activation of EMT by ALV-J and MDV, and enhanced cell proliferation, migration, and invasion. Subsequently, we revealed that DCLK1 physically interacted with β-catenin to promote the formation of the β-catenin-TCF4 complex, inducing transcription of the Wnt target gene, c-Myc, promoting EMT by increasing the expression of N-cadherin, Vimentin, and Snail, and decreasing the expression of E-cadherin. Taken together, we discovered that jointly activated DCLK1 by ALV-J and MDV accelerated cell proliferation, migration and invasion, and ultimately activated EMT, paving the way for tumor metastasis. This study elucidated the molecular mechanism underlying cooperative metastasis induced by co-infection with retrovirus and herpesvirus.

Tumor metastasis, a complex phenomenon in which tumor cells spread to new organs, is one of the greatest challenges in cancer research and is the leading cause of cancer-induced death. Numerous studies have shown that oncoviruses and their encoded proteins significantly affect metastasis, especially the EMT process. ALV-J and MDV are classic tumorigenic retrovirus and herpesvirus, respectively. We found that ALV-J and MDV synergistically promoted EMT. Further, we identified the tumor stem cell marker DCLK1 in ALV-J and MDV co-infected cells. DCLK1 directly interacted with β-catenin, promoting the formation of the β-catenin-TCF4 complex. This interaction activated the Wnt/β-catenin pathway, thereby inducing EMT and paving the way for synergistic tumor metastasis. Exploring the molecular mechanisms by which ALV-J and MDV cooperate during EMT will contribute to our understanding of tumor progression and metastasis. This study provides new insights into the cooperative induced tumor metastasis by retroviruses and herpesviruses.

The WNT6 ligand is a well-known activator of the WNT signaling pathway, considered a vital player in several important physiologic processes during embryonic development and maintaining homeostasis throughout life, regulating the proliferation and differentiation of multiple stem/progenitor cell types. More recently, as it is the case for many key molecular regulators of embryonic development, dysregulation of WNT6 has been implicated in cancer development and progression in multiple studies. In this review, we overview the most significant recent findings regarding WNT6 in the context of human malignancies, exploring its influence on multiple dimensions of tumor pathophysiology and highlighting the putative underlying WNT6-associated molecular mechanisms. We also discuss the potential clinical implications of WNT6 as a prognostic and therapeutic biomarker. This critical review highlights the emerging relevance of WNT6 in multiple human cancers, and its potential as a clinically-useful biomarker, addressing key unanswered questions that could lead to new opportunities in patient diagnosis, stratification, and the development of rationally-designed precision therapies.

Proline-rich tyrosine kinase 2 (PYK2) is involved in the occurrence, proliferation, migration, and invasion of various tumors. However, few studies have reported the role of PYK2 in colorectal cancer (CRC).

To explore the effects of PYK2 on CRC metastasis and elucidate the detailed molecular mechanisms involved.

The expression and prognosis value of PYK2 in CRC prognosis were analyzed using data from The Cancer Genome Atlas (TCGA). PYK2 was knocked down or overexpressed in human CRC cell line, HCT116. Cell proliferation, migration, invasion, and cycle changes were analyzed using CCK-8, Transwell, and flow cytometry assays. Western blotting and quantitative real-time PCR were performed to detect the mRNA and protein levels of cell proliferation and epithelial-mesenchymal transition (EMT) indicators. Fluorescence staining was performed to examine the cytoskeleton.

Lower expression of PYK2 was observed in CRC tissues and associated with poor prognosis and metastasis in patients with CRC in TCGA database. PYK2 knockdown significantly induced the migration and invasion of CRC cells but did not affect cell proliferation or cycle. Immunofluorescence staining of phalloidin showed that the downregulation of PYK2 increased the cytoskeleton in CRC cells. Moreover, low expression of PYK2 induced the downregulation of E-cadherin and upregulation of snail and vimentin by activating Wnt/β-catenin signaling, thus promoting EMT in CRC cells.

Low PYK2 expression was found in tumor tissues, especially metastases, and significantly correlated with patient prognosis. Moreover, decreased PYK2 induces EMT by activating Wnt/β-catenin signaling, which is the potential mechanism of CRC metastasis. Regulating the expression of PYK2 to suppress tumor cell metastasis may represent a promising therapeutic strategy for metastatic CRC.

The WNT/β-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/β-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT 'On' or 'Off' mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/β-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/β-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/β-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/β-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/β-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/β-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/β-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/β-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/β-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.

Glucocorticoids (GCs) are commonly used to treat sudden sensorineural hearing loss (SSNHL), although some patients are resistant to this therapeutic approach. Clinical studies have demonstrated the efficacy of tanshinone IIA (TA) in combination with GC for managing various human ailments. However, it remains unclear whether TA can mitigate GC resistance in SSNHL. Our aim is to elucidate the role of NRF2-induced transcriptional regulation of HDAC2 in influencing GC resistance and investigate the involvement of TA-related molecular pathways in GC resistance. Here, HEI-OC1 cells are treated with lipopolysaccharide (LPS) to establish an in vitro model for SSNHL. The cells are subsequently treated with dexamethasone (DXE) or DXE + TA. RT-qPCR and western blot analysis are used to measure the mRNA and protein levels of Forkhead box P3 (FOXP3), nuclear factor erythroid 2-related factor 2 (NRF2), and histone deacetylase 2 (HDAC2). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays are carried out to assess cell proliferation. Flow cytometry analysis is performed to evaluate apoptosis. Mechanistic studies involve chromatin immunoprecipitation (ChIP), luciferase reporter, and DNA pull-down assays. Our results show that treatment with TA + DEX significantly increases proliferation and suppresses apoptosis in LPS-treated HEI-treated OC1 cells. TA upregulates HDAC2 expression by activating NRF2-mediated transcription of HDAC2, with the NRF2-HDAC2 binding site located at bases 419-429 (ATGACACTCCA) in the promoter sequence of HDAC2. Furthermore, TA upregulates FOXP3 expression to activate NRF2 transcription, with the predicted FOXP3-binding site located at bases 864-870 (GCAAACA) in the promoter sequence of NRF2. In summary, these findings suggest that TA enhances the therapeutic effects of GC on the proliferation and apoptosis of HEI OC1 cells by increasing FOXP3/Nrf2 expression. These results indicate that TA may be promising for ameliorating GC resistance in patients with SSNHL.