Oral squamous cell carcinoma (OSCC) is a common heterogeneous oral malignancy (Wang. et al., 2021a). Smoking, excessive alcohol consumption, betel quid chewing, and human papilloma virus are risk factors for OSCC (Nokovitch et al., 2023). Approximately 600,000 patients are deeply troubled by OSCC each year, representing about 4% of all tumors (Pekarek et al., 2023). Oral cavity provides convenience for clinical examination, however the diagnosis of OSCC is in advanced stages due to misdiagnosis by the doctor or ignorance by patients (Jagadeesan et al., 2024). Meantime, the prognosis is unsatisfactory for patients with OSCC, the 5-year survival rate is as low as 40%–50% (Chai et al., 2020). Currently, the primary treatment modalities for OSCC include surgery, chemotherapy, and novel cellular therapies. While these are the mainstay of clinical management, their therapeutic efficacy remains suboptimal due to strong side effects, high costs of novel cellular therapies, and the propensity of OSCC cells (Jagadeesan et al., 2024). Therefore, there is a pressing need to increase survival rates and quality of life of OSCC patients by developing new and reliable prognostic evaluation method.

Disulfidptosis is a novel type of regulated cell death, which is associated with metabolic changes and has a strong effect on anti-tumor immune response (Liu et al., 2023). In addition, the metabolism of disulfides in cancer cells is connected with immune evasion, metastasis, and resistance of tumor cells (Shrihari et al., 2022; Wang et al., 2021b; Zhang et al., 2022a). As the source of programmed cell death, disulfidptosis is expected to provide a new approach to cancer therapy. So far, the role of disulfidptosis in OSCC is still quite lacking. Meanwhile, long non-coding RNAs (lncRNAs) are critical to the tumorigenesis and progression, and can be considered key factor to promotion and suppression of tumor due to their dysregulation in cancer (Ahmad et al., 2023; Kitajima et al., 2023). Currently, studies on the cell death patterns of OSCC have found that ferroptosis-related lncRNAs (Qiu et al., 2022), cuproptosis-related lncRNAs (Gong et al., 2024), and pyroptosis-related lncRNAs (Xin et al., 2022) are crucial prognostic biomarkers and therapeutic targets for OSCC. However, there is a lack of research on the role of disulfidptosis-related lncRNAs (DE-DRLs) in OSCC.

Here, we systematically structured a dependable DE-DRLs for predicting prognosis of OSCC, and explored the relationship between the prognostic model and clinicopathological information and the tumor immune landscape, and investigate the role of key DE-DRLs in OSCC. The implications of our findings are expected to generate guidance for tailoring personalized treatment strategies, and provide a foundation for further research on the mechanism of disulfidptosis in OSCC.

The lncRNAs sequencing information, which exclude samples origin from “hypopharynx”, “tonsil” or “larynx” of the TCGA-HNSC were acquired from the Cancer Genome Atlas (TCGA) database (https://portal.gdc.cancer.gov/), in which 14,071 lncRNAs were identified for the further analysis. The TCGA-HNSC comprised 337 tumor samples along with 32 control samples, samples that were not representative of the oropharyngeal region and that did not affect the prognosis of HPV were excluded, the clinical pathological information was shown in Supplementary Table S1. Additionally, 18 DRGs were obtained from the literature (Dong et al., 2023).

The OSCC patients face a poor prognosis, regulating disulfidptosis in cancer is a promising therapeutic approach (Yang et al., 2024). In this study, 9 DE-DRLs (AC009226.1, AP001107.9, AC108463.3, SAP30L_AS1, AC007406.3, PTPRN2_AS1, AP003559.1, JMJD1C_AS1, and AC079160.1) associated with OSCC were accurately identified. A prognostic model showed high-risk patients had lower survival. A nomogram integrating risk score and clinical features had excellent predictive ability for patient outcomes. DE-DRLs were linked to the OSCC immune microenvironment, where high levels of certain immune cells predicted poor survival. Additionally, 12 drugs differed in efficacy between risk groups, and immune checkpoints were more highly expressed in the low-risk group, pointing to potential therapeutic targets.

To prevent overfitting, we used LASSO regression to reduce the dimensionality of the data. We identified 9 DE-DRLs that were closely associated with the OS of OSCC patients and all highly expressed in tumor group of TCGA-HNSC. Several of the identified DE-DRLs have been previously characterized and are strongly associated with tumorigenesis and cancer progression. Specifically, AC009226.1 has been established as a prognostic biomarker for lung adenocarcinoma (LUAD), while AC007406.3 has been validated as a prognostic target in clear cell renal cell carcinoma (ccRCC). Both lncRNAs exhibit elevated expression levels in tumor tissues compared to normal counterparts, as reported in previous studies (Sun et al., 2023; Zhang et al., 2023b). In addition, JMJD1C_AS1 and AC079160.1 have been identified as potential prognostic biomarkers for gastric cancer (GC) (Ahmadpour Youshanlui et al., 2024; Guo et al., 2021). Notably, high expression of AC079160.1 has been correlated with favorable survival outcomes in GC patients, suggesting its role in predicting prognosis and potentially informing treatment strategies. These findings underscore the clinical relevance of these DE-DRLs across diverse cancer types and highlight their potential utility in precision oncology (Guo et al., 2021; Yang et al., 2022). Moreover, emerging evidence demonstrates that SAP30L-AS1 exhibits elevated expression levels in both prostate cancer (PCa) tissues and cell lines. Functionally, SAP30L-AS1 suppresses the upregulation of SAP30L in PCa, thereby exerting a tumorigenic effect. These findings, as previously reported (Qin et al., 2019), further highlighting its broad clinical relevance. PTPRN2_AS1 displayed consistent result with Xiong et al. (2023). Notably, this study represents the first report identifying AC108463.3 and AP003559.1 as prognostic markers for cancer, thereby addressing a critical void in the existing cancer prognosis literature. This groundbreaking discovery significantly expands the current knowledge base regarding potential cancer biomarkers. RT-qPCR analysis revealed elevated expression levels of AP001107.9 in the control group, diverging from the findings of prior investigations by Shen et al. (2025). This discrepancy may stem from two main factors: limited sample size causing heterogeneity and study-specific epigenetic/post-transcriptional regulation of AP001107.9. Uncharacterized regulatory mechanisms in prior research may explain expression variability and result divergence. Exploring DE-DRLs-prognosis correlations could offer new molecular targets for OSCC.

Systematically analyzing the biological pathways that lncRNAs may be involved in regulating will help us deepen our understanding of the pathological process of OSCC from multiple dimensions, from molecular mechanisms to clinical applications, providing dual support for target selection and efficacy prediction in the precise treatment of OSCC. Previous studies have shown that, the downregulation of SAP30L by SAP30L_AS1 impairs the assembly and enzymatic activity of the HDAC complex. This leads to dysregulated histone deacetylation, subsequent transcriptional repression of tumor-suppressor genes, and promotion of cancer cell proliferation (Qin et al., 2019). PTPRN2_AS1 can adsorb miR-145-5p through the ceRNA mechanism (Huang et al., 2021), thereby relieving its inhibition on PTPRN2 and enhancing the activity of the insulin signaling pathway, promoting tumor cell glycolysis (Meng et al., 2019), which also crucial in the energy metabolism reprogramming of OSCC. However, although no direct studies have confirmed the involvement of AC009226.1, AP001107.9, AC108463.3, AC007406.3, AP003559.1, JMJD1C_AS1, and AC079160.1 in the physiological processes of OSCC, evidence from the literature and the present study indicates that these lncRNAs may participate in biological pathways related to tumor proliferation (Cutilli et al., 2016), invasion (Wu et al., 2022), immune regulation (Huang et al., 2024), and epigenetics (Tang et al., 2021). DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, aberrant DNA methylation patterns are strongly associated with cancer, such as lncRNAs can recruit or repel DNA modifiers to specific gene targets and regulate the expression of DNA modifiers per se at multiple levels (Huang et al., 2022; Shen et al., 2017). This not only provides novel insights into the multi-dimensional regulatory mechanisms underlying OSCC progression but also lays a foundation for identifying potential prognostic biomarkers and therapeutic targets for OSCC.

While the OSCC pathogenesis also involves complex host-microenvironment interactions, and clinical challenges of advanced OSCC further highlight the need to expand lncRNA-related mechanism exploration to broader pathological and clinical contexts. Furthermore, previous studies have shown that the ecological imbalance of the oral microbiome caused by risk factors such as tobacco use, alcohol consumption, betel nut chewing, and HPV infections can lead to abnormal expression of lncRNAs in the oral cavity, which are associated with inflammatory mechanisms facilitating OSCC progression (Crispino et al., 2024; Mishra et al., 2025). More importantly, since OSCC patients were usually diagnosed at an advanced stage and are at risk of bone metastasis, which indicate a poor outcome (Wang et al., 2024). Nevertheless, there has been limited information on bone metastasis in OSCC (Wang et al., 2024). According to previous research results, inhibition of disulfidptosis can prevent osteoclast overactivation and, consequently, reduce the risk of bone metastasis in patients (Clézardin et al., 2021). This indicates that targeting disulfidptosis-related lncRNAs is expected to regulate the balance of intracellular disulfidptosis bond metabolism and the activity of osteoclasts at the molecular level, thereby blocking the colonization and invasion of tumor cells into bone tissue. This reminds us that by targeting the disulfidptosis-related lncRNAs screened in this study, we can not only inhibit the progression of the primary lesion of OSCC but also reduce the risk of bone metastasis, providing a new therapeutic target for improving the quality of life of patients with advanced OSCC.

At present, incorporating prognostic models into routine clinical practice can facilitate the estimation and quantification of patient prognosis (Hoesseini et al., 2022). The AUCs of prognostic genes for the OSCC by Li et al. at 1-year was 0.683 (Li et al., 2024) and Tang et al. was 0.752 (Tang et al., 2023), while our study result was 0.754. The nomogram represents a key medical advancement, addressing personalized healthcare needs by enabling clinicians to evaluate individual risk factors and prognosis for informed, tailored decisions (Balachandran et al., 2015), the slope of the calibration curve in this study was approximately equal to 1. This study validates the prognostic model and nomogram for accurately predicting OSCC outcomes. With high precision, these tools enhance risk stratification and evidence-based treatment decisions, improving patient management and personalized care.

Accumulating evidence from prior investigations has firmly established the indispensable role of immune cell infiltration in shaping the therapeutic response and clinical outcomes of patients with OSCC. In the present study, mast cells, activated NK cells, and Tregs emerged as key immune cell populations with significant implications for OSCC immunobiology and prognosis. This observation aligns with established literature demonstrating that tumor-infiltrating mast cells can modulate Treg activity to facilitate tumor progression, thereby undermining the host’s antitumor immune response (Lv et al., 2024). Consistently, elevated densities of activated NK cells and Tregs within the tumor microenvironment have been repeatedly associated with adverse clinical outcomes in OSCC patients (Lv et al., 2024; Wu et al., 2020). Our findings also corroborate previous reports indicating that a high TMB in OSCC patients portends a poorer prognosis and serves as a valuable biomarker for guiding treatment decisions in recurrent and metastatic disease (Lv et al., 2024). Notably, differential expression analysis revealed significantly higher levels of MYCBP2, TGFBR2, PLEC, and NSB1 in the high-risk cohort, suggesting potential roles for these genes in tumorigenesis and disease progression. In thyroid cancer (TC), MYC binding protein 2 (MYCBP2) has been linked to inflammatory cell infiltration and patient survival (Wang et al., 2022). TGFBR2, a central transducer of TGF-β - mediated growth inhibitory signals, has been implicated in the pathogenesis of multiple malignancies (Huang et al., 2014). PLEC has been identified as a promising biomarker and therapeutic target in pancreatic adenocarcinoma (PAAD) (Ge et al., 2024), while amplification of NSB1 has been shown to drive the pathobiology of uveal melanoma (UM) (Banimohammad et al., 2025). Collectively, these findings prompt the hypothesis that disulfidptosis may represent a critical mechanism underlying immune resistance and tumor immune escape in OSCC, offering novel insights into the complex interplay between cell death pathways and tumor immunobiology.

In recent years, cancer bioinformatics has emerged as a transformative force, driving advancements in anticancer drug development and personalized therapeutics while substantially enhancing the accuracy of cancer therapeutic prediction (Lu et al., 2017). Treatment resistance, a common occurrence in OSCC, substantially diminishes patient survival rates and profoundly impacts clinical treatment decisions (Cheng et al., 2021). Consequently, a comprehensive assessment of drug sensitivity in OSCC patients is imperative. In the present study, five drugs, including BMS-754807_2171, AZD8055_1059, Epirubicin_1511, Mitoxantrone_1810, and Foretinib_2040, were identified as upregulated in the high-risk group. These findings may help elucidate the mechanisms underlying the poor prognosis observed in this subgroup. Previous research has shown that BMS-754807 potentiates the efficacy of chemotherapeutic agents in lung cancer cells by inducing autophagy, cell cycle arrest, and growth inhibition, ultimately leading to synergistic cytotoxicity (Zhang and Zhou, 2025). Similarly, Yin et al. (2024) reported consistent IC₅₀ expression of BMS-754807 in gastric adenocarcinoma (STAD) in their study on lactylation-related gene sets and mitochondrial functions in STAD (Yin et al., 2024). AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity (Chresta et al., 2010), AZD8055_1059 had been verified as a drug treatment target in non-small cell lung cancer (Shi et al., 2025). While, the Epirubicin was already used in clinical research for non-small cell lung cancer as early as 1997 by Colucci et al. (1997). Furthermore, Foretinib, a multikinase inhibitor, has been clinically employed in the treatment of breast carcinoma (BC) (Anitha et al., 2023) and Mitoxantrone_1810 had also been proven to have a higher expression level in the high-risk group of HNSCC (Zhu et al., 2022). Collectively, the results of this study provide a theoretical foundation for the development of personalized treatment strategies for OSCC patients.

In the current investigation, transcriptomic data integrated with advanced bioinformatics methodologies were utilized to systematically identify 9DE-DRGs, namely, AC009226.1, AP001107.9, AC108463.3, SAP30L_AS1, AC007406.3, PTPRN2_AS1, AP003559.1, JMJD1C_AS1, and AC079160.1, as differentially expressed in OSCC. A prognostic model and nomogram showed strong predictive value for patient outcomes, aiding clinical risk stratification. Immune microenvironment analysis revealed interactions between cell death pathways and tumor immunobiology. Drug prediction identified BMS-754807_2171 and Foretinib_2040 as potential therapies. Limitations include data quality, algorithm assumptions, and reliance on RT-qPCR validation, necessitating independent clinical validation across cohorts to confirm biomarkers utility in OSCC management.