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Results for “Oral squamous cell carcinoma (OSCC)”

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PubMed2022

Krüppel-like factor 5 promotes the progression of oral squamous cell carcinoma via the baculoviral IAP repeat containing 5 gene.

BACKGROUND: Krüppel-like factor 5 (KLF5) is highly expressed in a variety of tumors, and our study aimed to investigate the role of KLF5 in oral squamous cell carcinoma (OSCC). METHODS: To explore the differential expression of KLF5, next-generation sequencing (NGS) and further analyses were conducted in paired premalignant and tumor tissues and adjacent normal mucosa. We then analyzed the mRNA expression data from The Cancer Genome Atlas (TCGA) and performed gene set enrichment analysis (GSEA) to predict the function of KLF5. Small interfering RNA (siRNA) targeting KLF5 was used to knock down its expression in cells and further evaluate the changes in cell apoptosis, proliferation, and migration. We predicted whether baculoviral inhibitor of apoptosis protein (IAP) repeat containing 5 (BIRC5) was the potential target gene of KLF5 via the NCBI and JASPAR databases. Furthermore, we analyzed BIRC5 expression after KLF5 knockdown and explored its function in athymic BALB/c nude mice. RESULTS: KLF5 expression in clinical samples gradually increased from normal mucosa tissues to premalignant and then to OSCC tissues. Analysis of TCGA data and GSEA also suggested that KLF5 was expressed at higher levels in OSCC and involved apoptosis and the protein 53 (P53), transforming growth factor-β (TGF-β), and wingless/integrated (Wnt) signaling pathways. Cell apoptosis was promoted, whereas proliferation and migration were inhibited after KLF5 knockdown. Furthermore, we found KLF5 transcription binding sites on the BIRC5 promoter and BIRC5 expression was inhibited after suppressing KLF5 in vitro and in vivo. CONCLUSIONS: Our findings indicate that KLF5 promotes the development of OSCC via BIRC5, and could be a potential diagnostic and therapeutic target for OSCC.

Krüppel-like factor 5 (KLF5)↗

PubMed2024

Exploring the prognostic landscape of oral squamous cell carcinoma through mitochondrial damage-related genes.

Oral squamous cell carcinoma (OSCC), the most prevalent form of oral cancer, poses significant challenges to the medical community due to its high recurrence rate and low survival rate. Mitochondrial Damage-Related Genes (MDGs) have been closely associated with the occurrence, metastasis, and progression of OSCC. Consequently, we constructed a prognostic model for OSCC based on MDGs and identified potential mitochondrial damage-related biomarkers. Gene expression profiles and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Differential analysis was conducted to identify MDGs associated with OSCC. COX analysis was employed to screen seven prognosis-related MDGs and build a prognostic prediction model for OSCC. Cases were categorized into low-risk or high-risk groups based on the optimal risk score threshold. Kaplan-Meier (KM) analysis revealed significant survival differences (P < 0.05). Additionally, the area under the ROC curve (AUC) for patient survival at 1 year, 3 years, and 5 years were 0.687, 0.704, and 0.70, respectively, indicating a high long-term predictive accuracy of the prognostic model. To enhance predictive accuracy, age, gender, risk score, and TN staging were incorporated into a nomogram and verified using calibration curves. Risk scoring based on MDGs was identified as a potential independent prognostic biomarker. Furthermore, BID and SLC25A20 were identified as two potential independent mitochondrial damage-related prognostic biomarkers, offering new therapeutic targets for OSCC.

Humans↗

PubMed2026

Transcriptome-based epigenetic screening identifies DNA hypermethylation signatures as prognostic biomarkers in oral squamous cell carcinoma.

Promoter DNA hypermethylation is a key epigenetic mechanism of gene silencing in cancer, yet the DNA hypermethylome of oral squamous cell carcinoma (OSCC) and its prognostic relevance remain poorly characterized. Here, we systematically identified and validated novel hypermethylated genes with prognostic significance in OSCC using a genome-wide discovery and multi-platform validation strategy. Candidate genes were first identified by pharmacologic demethylation combined with RNA sequencing across OSCC cell lines, then validated by quantitative RT-PCR, methylation-specific PCR, and bisulfite sequencing in OSCC cell lines, normal oral mucosa, and primary OSCC tumors, with independent confirmation in the TCGA-HNSC dataset. Immunohistochemistry confirmed protein-level silencing, and Kaplan-Meier survival analysis assessed prognostic significance across both cohorts. This pipeline identified five candidate genes, GPX3, ANG, CTGF, GPRC5B, and BAMBI, exhibiting cancer-specific promoter hypermethylation associated with transcriptional and protein silencing in OSCC. Validation in oral cavity tumor samples extracted from the TCGA-HNSC dataset confirmed tumor-specific hypermethylation and revealed significant inverse correlations between methylation and expression for GPX3, GPRC5B, and CTGF. Notably, CTGF hypermethylation was independently associated with poor overall survival in both cohorts (institutional cohort, p=0.03; oral tumor subset from TCGA-HNSC, p=0.01), and a combined ANG+CTGF methylation signature showed superior and reproducible prognostic performance across both platforms. Pathway analysis linked these genes to epithelial-mesenchymal transition and interferon response signaling. This study establishes the first validated DNA methylation biomarker panel for OSCC prognosis, identifying CTGF hypermethylation as a robust prognostic driver with translational potential for clinical risk stratification.

Humans↗

PubMed2026

ceRNA network of lncRNAs and mRNAs in OSF-to-OSCC progression: Diagnostic biomarkers and functional pathways.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic potentially malignant disorder that can progress to oral squamous cell carcinoma (OSCC). Although dysregulated non-coding RNAs have been implicated in oral carcinogenesis, the competing endogenous RNA (ceRNA)-mediated regulatory mechanisms underlying OSF-to-OSCC progression remain poorly understood. This study aimed to identify candidate regulatory molecules and construct a putative lncRNA-miRNA-mRNA network associated with malignant transformation. METHODS: Publicly available microarray datasets (GSE117973 and GSE125866) were analyzed to identify differentially expressed genes between OSF and OSCC. Differentially expressed transcripts were classified into mRNAs and lncRNAs based on public transcript annotations. Highly correlated lncRNA-mRNA pairs were identified using Pearson correlation analysis and integrated with multiMiR-supported miRNA-mRNA interactions obtained from public databases to construct a putative ceRNA regulatory network. Functional characterization focused on apoptosis, epithelial-mesenchymal transition (EMT), and immune checkpoint-related pathways. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance, and selected biomarkers were externally validated using The Cancer Genome Atlas (TCGA) OSCC cohort. RESULTS: Integrated transcriptomic analysis identified several dysregulated mRNAs and lncRNAs associated with OSF-to-OSCC progression. Network analysis highlighted TBC1D3B, RREB1, TEAD3, SREBF1, TMEM41B, FOXK2, and KIAA1958 as prominent hub genes within the putative regulatory network. Functional analyses demonstrated significant associations with apoptosis-, EMT-, and immune checkpoint-related genes, suggesting potential involvement in multiple biological processes contributing to malignant transformation. Several hub genes exhibited strong diagnostic performance, with ROC analysis yielding AUC values ranging from 0.891 to 1.000, indicating excellent discrimination between OSF and OSCC samples. External validation using TCGA further supported the relevance of the identified biomarkers in OSCC. CONCLUSIONS: This study provides a comprehensive transcriptomic framework describing putative lncRNA-miRNA-mRNA regulatory interactions associated with OSF progression to OSCC. The identified hub genes and regulatory networks represent candidate biomarkers for early detection and provide a foundation for future mechanistic and experimental validation. As the proposed ceRNA interactions are computationally inferred, further biological validation is required before clinical application.

RNA, Long Noncoding↗

PubMed2026

Structure-based virtual screening, multi-score docking, and molecular dynamics simulation of novel small molecules targeting the epidermal growth factor receptor for potential management of oral squamous cell carcinoma.

UNLABELLED: Oral squamous cell carcinoma (OSCC) is a major global health burden, with epidermal growth factor receptor (EGFR) serving as an important therapeutic target. However, resistance to currently available EGFR inhibitors limits the efficacy of long-term treatment. In this study, a structure-based virtual screening approach was employed using the Mcule database to identify novel small molecules with potential EGFR-inhibitory activity. The top-ranked compounds were subjected to consensus docking using multiple docking platforms and compared with established EGFR inhibitors. The most promising complexes were further evaluated using 500 ns molecular dynamics simulations to investigate their structural stability, conformational flexibility, and binding persistence. ADMET and pharmacokinetic analyses were performed to assess the drug-like and safety profiles. Five lead compounds (C1-C5) demonstrated significant binding affinities toward EGFR, ranging from - 9.9 to - 9.2 kcal/mol, while satisfying the major drug-likeness criteria. Molecular dynamics simulations suggested that C1 and C4 may form relatively stable EGFR-ligand complexes, as supported by stable RMSD convergence and persistent interactions with key active-site residues throughout the simulation period. Trajectory-based interaction analyses further indicated a sustained binding behavior. ADMET profiling predicted favorable oral bioavailability and low predicted toxicity for most compounds, particularly C3 and C5, although a potential risk of cytochrome P450-mediated drug-drug interactions was observed. Overall, the shortlisted compounds exhibited docking and dynamic stability profiles comparable to those of the reference inhibitor Lapatinib. These findings suggest the potential therapeutic relevance of structurally novel EGFR-targeting scaffolds in OSCC and provide a foundation for future experimental validation through in vitro and in vivo studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00722-4.

ADMET↗

PubMed2026

The prognostic value and molecular mechanisms of Porphyromonas gingivalis infection-associated differentially expressed genes in oral squamous cell carcinoma.

BACKGROUND: Increasing evidence suggests that Porphyromonas gingivalis (Pg) is associated with oral squamous cell carcinoma (OSCC) development and progression. This study aimed to identify Pg-associated genes with prognostic relevance in OSCC through integrated bioinformatics analysis. METHODS: OSCC-related differentially expressed genes (DEGs) were identified from the The Cancer Genome Atlas (TCGA)-OSCC cohort and intersected with Pg supernatant-associated DEGs from GSE192887. Raw count data were analyzed with DESeq2, whereas transcripts per million (TPM)-transformed expression values were used for downstream visualization and model construction. Weighted gene co-expression network analysis (WGCNA), univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and multivariable Cox modeling were used to develop a seven-gene prognostic signature, which was externally evaluated in GSE41613. Additional analyses examined treatment-associated expression changes in the seven model genes, pairwise correlations among the model genes, and correlations between Pg supernatant-associated differentially expressed gene (PgSDEG)-derived module eigengenes and immune-cell fractions. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed in eight paired OSCC and adjacent non-tumor tissues and in supplemented-brain heart infusion (BHI) vehicle-control and Pg culture-supernatant-treated HOK, HSC-3, and CAL-27 cells. RESULTS: A prognostic signature comprising CXCL8, GAST, HBQ1, PADI3, STC1, TEX19, and TMEM92 was established. The signature showed limited-to-moderate discrimination in the TCGA training cohort, with 1-, 3-, and 5-year areas under the curve (AUCs) of 0.68, 0.69, and 0.69, respectively, and limited discrimination in the GSE41613 external cohort (AUCs: 0.66, 0.67, and 0.61). Kaplan-Meier analysis showed poorer survival in the high-risk group in both cohorts. The GSE192887 analysis showed significant treatment-associated expression changes in all seven genes after Pg culture-supernatant exposure. In paired tissues, CXCL8 and TMEM92 were significantly higher in OSCC tissues, whereas STC1 was not significant after Holm correction. In CAL-27 cells, CXCL8, STC1, and TMEM92 increased significantly after culture-supernatant treatment, whereas the corresponding comparisons were not significant in HOK or HSC-3 cells after adjustment. CONCLUSIONS: This study developed a seven-gene Pg-associated prognostic signature for OSCC and provided complementary transcriptomic, immune-correlation, tissue, and cell-based evidence that placed the signature in biological context. The model showed limited-to-moderate discrimination and is not ready for clinical use. The enrichment, gene-correlation, and immune-correlation findings are hypothesis-generating rather than mechanistic evidence. Further independent validation and dedicated functional studies are required.

Oral squamous cell carcinoma (OSCC)↗

PubMed2026

Association of HPV16 infection with p53 and survivin expression in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and a major public health concern worldwide. This study aimed to investigate the relationship between p53 and survivin expression, clinicopathologic parameters and HPV16 infection in OSCC in order to elucidate the potential role of HPV16 in its pathogenesis.The study enrolled 45 patients who underwent surgical treatment for histologically confirmed OSCC. Tumor specimens were formalin-fixed and paraffin-embedded (FFPE) and histologically analyzed using hematoxylin/eosin staining. Immunohistochemistry for p53 and survivin was performed using the DAKO system. DNA extracted from FFPE tumor tissues was analyzed for HPV16 genome presence using polymerase chain reaction (PCR). All patients were followed for three years after primary treatment.No statistically significant associations were observed between p53 or survivin expression and clinicopathologic parameters including age, gender, tumor site, grade, stage, recurrence, metastasis or HPV16 status (P > 0.05). Among HPV16-positive patients (11/45, 24.4%), low survivin expression (<5%) was found in 8/11 (73%) patients, while high p53 expression (>10%) was observed in 7/11 (64%) patients. Disease-free interval did not differ significantly between patients with low vs. high p53 (P = 0.220) or survivin expression (P = 0.580). A significant correlation was detected between p53 and survivin expression (P = 0.04). HPV16 positivity was significantly associated with the absence of p53 immunoreactivity.These findings suggest that HPV16-independent oncogenic pathways are likely predominant in OSCC, while HPV16 infection may be associated with a distinct molecular subset characterized by absent p53 expression (p53-; survivin+/-; HPV16+). These results underscore the biological heterogeneity of OSCC and may have implications for future biomarker-based stratification of patients.

HPV16↗

PubMed2026

Synthesis of Padina boergesenii-Derived Zinc Oxide Nanoparticles and their Therapeutic Potential Against Oral Squamous Cell Carcinoma: A Transcriptomic and in Vitro Evaluation.

Cancer remains a major health challenge, with oral squamous cell carcinoma (OSCC) being an high aggressive subtype of head and neck squamous cell carcinoma that lacks effective therapeutic options. Current study integrates the synthesis of zinc oxide nanoparticles (ZnO-NPs) from the marine brown algae Padina boergesenii with the OSCC gene expression profile to evaluate their potential therapeutic effects against OSCC. Herein, the ZnO-NPs from Padina boergesenii were prepared through the green synthesis method. The obtained ZnO-NPs were characterized through spectroscopic methods, the UV spectrophotometer shows maximum absorbance at 372 nm, FT-IR presents Zn-O functional band at 516 cm- 1, HR-TEM confirms average particle size of 55.70 nm and the Zetasizer shows zeta potential of + 12.9 mV, indicating colloidal stability. The cytotoxicity assay with ZnO-NPs against oral cancer cell lines exhibited a reduction in cell viability at IC₅₀ value of 20 µg/mL. Meanwhile, the transcriptome analysis of OSCC highlights that MYC, STAT3, BRCA1, and AKT1 are the OSCC therapeutic targets involved in proliferation, immune evasion, genomic instability, and cancer signalling pathways. Further, qRT-PCR based gene expression analysis demonstrates significant down-regulation of these targets upon ZnO-NPs treatment in KB cell lines. Overall, this study emphasizes the anticancer potential of Padina boergesenii-derived ZnO-NPs that could effectively modulate the therapeutic targets and may benefit the treatment of OSCC cancer.

Cytotoxicity↗

PubMed2025

Exogenous BMI1 expression aggravates oral squamous cell carcinomas in tongue epithelia.

Oral squamous cell carcinoma (OSCC) is characterized by aggressiveness and a poor prognosis, in part because most patients are diagnosed during the later stages of the disease. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), part of polycomb repressive complex 1 (PRC1), is a key transcription factor overexpressed in OSCC. Although increased BMI1 has been linked to tumor formation in mouse models of the disease, the molecular mechanisms have not been elucidated. Here we used a transgenic mouse line (KrTB) that selectively overexpresses BMI1 in the tongue basal epithelial stem cells (SCs) to delineate BMI1 actions during oral tumorigenesis. By tumor pathological classification after 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis we detected more severe tumors in mice with ectopic BMI1 expression. Genome-wide transcriptomics indicated that mRNAs associated with human OSCC, including SOX9, HIF1A, MMP9, INHBB, and MYOF, were further increased by ectopic BMI1 expression in murine tongue epithelia. mRNAs encoding multiple metabolic targets, such as SLC2A1 (GLUT1), PKM, LDHA, and HK2, were also increased upon BMI1 overexpression in 4-NQO-treated tongue epithelia. Furthermore, we detected BMI1, SOX9, and GLUT1 proteins in the infiltrating cells of invasion fronts identified by markers of invasive SCCs. Finally, metabolomic data show that BMI1 overexpression in tongue epithelia promotes glycolysis during 4-NQO-induced carcinogenesis. Thus, our data demonstrate that BMI1 causes OSCC cells to alter cell metabolism, as changes in many of these transcripts are linked to increased glycolysis and metabolic reprograming that occurs during carcinogenesis.

Animals↗

PubMed2026

A novel neoadjuvant immunotherapy confers improved overall survival in oral cancer patients with low tumor PD-L1 expression The IT-MATTERS Clinical trial - Prognostic role of tumor PD-L1 expression.

OBJECTIVE: Five-year overall survival (OS) remains < 50% for patients with resectable, locally advanced (LA) primary oral squamous cell carcinoma (OSCC) and soft palate, receiving current standard of care (SOC). The aim of our study was to examine neoadjuvant Leukocyte Interleukin Injection (LI) with CIZ (intravenous low dose cyclophosphamide, indomethacin and zinc multivitamins) effect on OS, in low-risk (LR) OSCC patients. PATIENTS AND METHODS: In a randomized, controlled Phase 3 trial, treatment-naïve locally advanced patients, with stage III/IVa OSCC and soft-palate cancer, had surgical tumor samples assessed for pre-defined thresholds of PD-L1 tumor proportion score (TPS). OS was analyzed using proportional hazard models for LI + CIZ + SOC vs SOC, in the intention-to-treat (ITT) population. RESULTS: OS was superior in low risk (LR) patients receiving LI + CIZ + SOC compared to SOC; OS advantage hazard ratio (HR) 0.64, p = 0.0569 (without selecting for N0, PD-L1 TPS < 10%), and the Kaplan-Meier (K-M) lifetable achieved significance (log rank p = 0.0340) favoring LI + CIZ + SOC vs SOC. Applying the selection criteria (cN0 and TPS < 10%) to ITT, OS reached HR 0.34p = 0.0012, Kaplan-Meier log rank p = 0.0015. The ITT LR cohort (cN0 and TPS < 10%) achieved a HR 0.26 (p = 0.0023), Kaplan-Meier log rank p = 0.0013, supported by progression free survival (PFS) HR 0.43, p = 0.0178, Kaplan-Meier log rank p = 0.0431, with 32% absolute survival advantage over control at 60 months. CONCLUSIONS: Significant OS prolongation was observed in ITT population for LI + CIZ + SOC vs SOC, in LR and in ITT LR cN0, PD-L1TPS < 10% cohort having locally advanced squamous cell carcinoma tumors in oral cavity/soft-palate. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01265849; EudraCT (Identifier: 2010-019952-35).

Humans↗

PubMed2025

NEK9-mediated Wnt signalling repressor TLE3 rewires Docetaxel resistance in cancer cells by inducing pyroptosis.

BACKGROUND: Docetaxel is the most common chemotherapy regimen for several neoplasms, including advanced OSCC (Oral Squamous Cell Carcinoma). Unfortunately, chemoresistance leads to relapse and adverse disease outcomes. METHODS: We performed CRISPR-based kinome screening to identify potential players of Docetaxel resistance. Immunohistochemistry was performed to examine the expression profile of the target gene across tumour tissues. Global transcriptome analysis was performed to determine the molecular mechanism underlying Docetaxel resistance. NEK9 kinase assay was performed to identify a putative kinase inhibitor. RESULTS: Upon conducting CRISPR-based kinome screening, Never In Mitosis Gene-A Related Kinase-9 (NEK9) was identified as a major player of Docetaxel resistance in OSCC, prostate, and pancreatic cancer lines. NEK9 expression was found to be upregulated in chemotherapy non-responder OSCC patients as compared to responders. NEK9 ablation restores Docetaxel-induced cell death in chemoresistant cells. Mechanistically, we found that NEK9 deletion upregulates Transducin-like enhancer protein 3 (TLE3), which in turn represses Wnt signalling. Fostamatinib was identified as a potent NEK9 inhibitor that overcomes Docetaxel resistance. CONCLUSIONS: Our study demonstrated that NEK9 plays an important role in Docetaxel resistance. The novel combination of NEK9 inhibitor Fostamatinib and Docetaxel needs further clinical investigation in advanced OSCC.

Humans↗

PubMed2026

Multi-omics Approaches to CCAAT/Enhancer-Binding Protein Beta in Oral Squamous Cell Carcinoma: Crosstalk Between Tumor Cells and Tumor-Associated Macrophages Driving Disease Progression.

BACKGROUND: CCAAT/Enhancer-Binding Protein Beta (CEBPB) is an important transcription factor that regulates tumor progression. However, the mechanism by which CEBPB regulates the progression of Oral Squamous Cell Carcinoma (OSCC) remains incompletely understood. Tumor progression depends on complex intercellular interactions within the tumor microenvironment. The purpose of this study was to investigate the role and epigenetic regulatory mechanisms of CEBPB in interactions between OSCC cells and tumor-infiltrating immune cells. METHODS: Bulk RNA-seq, ChIP-seq, and scRNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. The HOMER algorithm was employed to identify enhancers and predict the CEBPB-binding motif. Cell cluster analysis, functional enrichment, and intercellular interaction analysis were performed using the "Seurat" R package. H3K27ac enrichment at GAS6 enhancers was validated by ChIP-qPCR. Metastatic OSCC cells with CEBPB knockdown or GAS6 overexpression were established and co-cultured with THP-1 cells. IL-10 and IL-6 secretion from co-cultured THP-1 cells was detected via ELISA. Chemotaxis of OSCC cells toward THP-1 cells was assessed through a Transwell assay. RESULTS: CEBPB was upregulated in OSCC and correlated with poor prognosis. By integrating H3K27ac ChIP-seq and bulk RNA-seq data, 131 CEBPB-regulated enhancer-controlled genes were identified in lymph node metastatic OSCC cells. scRNA-seq analysis revealed eight major cell clusters in primary foci and lymph node metastases, including T/NK cells, malignant epithelial cells, B/plasma cells, macrophages, fibroblasts, dendritic cells, endothelial cells, and mast cells, with the malignant epithelial cells stratified into distinct sub-clusters. CEBPB expression was elevated in malignant epithelial cells of lymph node metastases compared to primary foci. Furthermore, 15 pairs of enhanced ligand-receptor interactions were identified in lymph node metastases relative to primary foci. GAS6 was a CEBPB-regulated enhancer-controlled gene, primarily mediating interactions between malignant cells and macrophages. CEBPB knockdown in metastatic OSCC cells significantly impaired their chemotaxis toward cocultured THP-1 cells, and downregulated IL-10/IL-6 secretion and CD206 expression in cocultured THP-1 cells. Conversely, GAS6 overexpression reversed these inhibitory effects. CONCLUSION: CEBPB activated GAS6 transcription in metastatic OSCC cells. The CEBPB/ GAS6 axis in metastatic OSCC cells enhanced their chemotaxis toward macrophages and promoted the M2 polarization of macrophages, thereby facilitating the establishment of an immunosuppressive microenvironment.

Humans↗

PubMed2025

Ferroptosis in Oral Cancer: Mechanistic Insights and Clinical Prospects.

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management.

Humans↗

PubMed2026

A Biomimetic Dual-Targeting Nano-APA-Editor Reprograms the 3'UTR Landscape for Tongue Squamous Cell Carcinoma Therapy.

Targeting post-transcriptional dysregulation of tumor suppressors represents a new frontier in cancer therapy. Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a pivotal therapeutic target in oral squamous cell carcinoma (OSCC). NUDT21 is highly upregulated, correlating strongly with poor survival and advanced clinical stage. We outline a pathogenic mechanism whereby NUDT21 drives this phenotype by forcing a network of tumor suppressor transcripts, notably PTEN, into translationally-repressed, long-3'UTR isoforms. To therapeutically "re-engineer" this APA switch, we design a "Nano-APA-editor." This platform features an HMSN core with an sgRNA-NUDT21 payload and a hierarchical targeting strategy: a cancer-educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, "gated" by a TA-aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short-3'UTR isoforms. Consequently, the Nano-APA-editor effectively reinstates PTEN and associated suppressors and inhibits multiple malignant phenotypes in vitro. In an orthotopic OSCC model, it demonstrates profound tumor regression, outperforming conventional chemotherapy (PTX) with excellent biocompatibility. In vivo analysis confirmed target engagement (NUDT21-down) and functional restoration (PTEN-, WEE1-, TGF-β-up). This work validates a "post-transcriptional re-engineering" strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.

Humans↗

PubMed2026

The astragaloside-brucea javanica oil nanoemulsion inhibiting the progression of oral squamous cell carcinoma through CDK1- HOXC10-MTFR2 pathway.

OBJECTIVE: This study aimed to investigate whether Astragaloside-Brucea javanica oil nanoemulsion (AS/BJO-NEs) inhibits the malignant progression of oral squamous cell carcinoma (OSCC) and to further explore its potential regulatory mechanisms. METHODS: Immunohistochemistry (IHC) was used to evaluate the expression of related pathway proteins in human OSCC and adjacent normal tissues. Stable OSCC cell lines with knockdown or overexpression of CDK1/HOXC10 were established. The effects of AS/BJO-NEs and the underlying mechanisms were assessed in vitro through colony formation, wound healing, and Transwell invasion assays, as well as RT-qPCR, western blot, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. An OSCC subcutaneous xenograft model in nude mice was constructed for in vivo validation using RT-qPCR, western blot, hematoxylin and eosin (H&E) staining, and IHC. RESULTS: Analysis of clinical samples revealed upregulated expression of CDK1, P-EZH2, HOXC10, MTFR2, and N-cadherin, alongside downregulated expression of H3K27me3 and E-cadherin in OSCC tissues. In vitro experiments confirmed that AS/BJO-NEs downregulated CDK1 in a concentration-dependent manner, subsequently reducing the expression of P-EZH2, HOXC10, and MTFR2, increasing H3K27me3 levels, and inhibiting cell proliferation, migration, and invasion. H3K27me3 was enriched in the HOXC10 promoter region, and HOXC10 directly bound to and activated MTFR2 transcription. In vivo experiments demonstrated that AS/BJO-NEs effectively inhibited tumor growth, regulated molecules within this pathway and epithelial-mesenchymal transition (EMT) markers, whereas CDK1 overexpression counteracted these effects CONCLUSION: This study demonstrates that AS/BJO-NEs exert anti-OSCC effects by inhibiting CDK1, downregulating HOXC10, thereby reducing MTFR2 expression, and suppressing cell proliferation, migration, invasion, and the EMT process.

Squamous Cell Carcinoma of Head and Neck↗

PubMed2026

Alternative End Joining Dependency Imposed by miR-21-5p Defines Radiation Resistance and a Targetable Vulnerability in Oral Squamous Cell Carcinoma.

PURPOSE: Clinical control of oral squamous cell carcinoma (OSCC) is constrained by heterogeneous radiosensitivity driven by divergent DNA damage response programs. The architecture and functional contribution of alternative end joining (Alt-EJ), an error-prone DNA double-strand break (DSB) repair pathway frequently upregulated in cancer, to radiation resistance remains poorly defined. METHODS AND MATERIALS: We profiled microRNAs in radioresistant OSCC clones and performed multiomic integration across an institutional OSCC cohort, an external OSCC cohort from the Gene Expression Omnibus, The Cancer Genome Atlas pan-cancer tumors, and cell lines characterized by Sanger Genomics of Drug Sensitivity in Cancer to infer DNA damage response characteristics, genomic scar features, drug sensitivity, and radiation therapy outcomes. DSB repair capacity and pathway usage were validated using functional assays, including Alt-EJ reporters and droplet digital PCR quantification of microhomology-mediated repair events. Core Alt-EJ effectors such as PARP1 and POLQ were perturbed genetically and pharmacologically. Therapeutic efficacy of PARP or POLQ inhibition with or without irradiation was tested in a syngeneic OSCC model, followed by bulk tumor transcriptomics to assess pathway engagement. RESULTS: Upregulation of miR-21-5p was not only selectively detected in radioresistant OSCC, but also modulated radiosensitivity in vitro and in vivo, and was associated with inferior postradiation therapy survival. A calibrated miR-21-5p target-gene signature tracked Alt-EJ activity across patient and mouse tumors and cancer cell lines, correlated with microhomology-mediated indels and broader genomic scarring, and predicted sensitivity to clinically available PARP inhibitors. Functionally, enforced miR-21-5p expression increased Alt-EJ usage and accelerated DSB repair, whereas inhibition or depletion of key Alt-EJ effectors reduced repair efficiency and restored radiosensitivity. In vivo, Alt-EJ targeting with PARP or POLQ inhibitor abrogated miR-21-5p-driven radiation resistance; transcriptomic profiling supported suppression of Alt-EJ programs as the operative mechanism. CONCLUSIONS: These findings establish a mechanistic link between miR-21-5p activity and Alt-EJ dependence, provide a clinically deployable signature to identify Alt-EJ-dependent OSCC, and support rational combinations of Alt-EJ targeting agents with radiation therapy to overcome treatment failure and advance precision radiation oncology.

MicroRNAs↗

PubMed2026

Newly identified invasion drivers define the tumor front in oral squamous cell carcinoma.

Cells at the invasive front of oral squamous cell carcinoma (OSCC) occupy a partial epithelial-to-mesenchymal transition (p-EMT) state that drives invasion and therapeutic resistance yet remains poorly understood. To define the regulators of this metastable state, we developed an isogenic OSCC model that captures stable epithelial and p-EMT phenotypes and used it to perform a genome-wide CRISPR invasion screen. This unbiased strategy identified 17 modulators of invasion, most previously unrecognized in cancer and virtually unexplored in OSCC, that converge on cytoskeletal remodeling, adhesion, and epigenetic regulation. Within this network, EDIL3 emerged as a central driver of EMT, invasion, and chemoresistance in head and neck cancer, extending prior reports in other tumor types. Importantly, the invasion signature derived from our screen localized with striking specificity to the tumor invasive front of human OSCC, providing direct clinical validation. Together, these findings reveal a novel, targetable network of transient invasion drivers defining the OSCC tumor front.

Journal Article↗

PubMed2025

Analysis of genomic traits of oral and laryngeal cancer: A comparative study.

Oral and laryngeal cancers exhibit overlapping clinical features but distinct genomic profiles. In a study of 60 Head and neck squamous cell carcinomas(HNSCC) cases (30 OSCC, 30 LSCC), NGS revealed TP53 mutations in 70% of oral squamous cell carcinoma (OSCC) and 83% of laryngeal squamous cell carcinoma (LSCC). CDKN2A alterations were more common in OSCC (40%) than LSCC (20%), while PIK3CA mutations were higher in LSCC (30%). NOTCH1 mutations were more frequent in OSCC (27%) than LSCC (10%). Pathway analysis showed disruptions in p53 and PI3K-Akt, with stronger enrichment in LSCC (ES: 3.42). The results suggest site-specific tumor biology influencing therapeutic targets. Molecular profiling is crucial for precision treatment in head and neck cancers.

Oral cancer↗