Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers all around the world with around 890,000 new cases and 450,000 mortalities annually (Bray et al., 2024, Johnson et al., 2020). The well-acknowledged risk factors accounting for HNSCC occurrence include tobacco-derived carcinogens exposure, excessive alcohol consumption, and human papillomavirus (HPV) infection. Despite the remarkable progression in the diagnosis and treatment of HNSCC over the past decades, the outcome remains unsatisfying, and the five-year survival rate is about 60 % (Chow, 2020, Johnson et al., 2020). Several clinicopathological parameters including primary tumor size, cervical lymph node metastasis, and clinical/pathological stage have been routinely conducted to evaluate the disease status and patients’ outcome and guide the clinical therapy of HNSCC (Amin et al., 2017, Huang and O'Sullivan, 2017). Nevertheless, these well-established clinicopathological parameters are far from optimal for the complexity and heterogeneity of HNSCC. Thus, developing an accurate and effective biomarker, that can be conveniently utilized in patients, is urgently needed to enhance patient stratification and advance precision oncology in clinical settings.

DNA damage response (DDR) is a critical cellular process that maintains genomic stability by detecting and correcting damage to the DNA molecules. This process involves a variety of mechanisms, including direct reverse repair, base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination /nonhomologous end joining double-strand break repair, each targeting specific types of DNA damage (Huang and Zhou, 2021, Jackson and Bartek, 2009). By accurately repairing DNA lesions, these mechanisms prevent mutations, maintain genetic integrity, and protect against genetic diseases like cancer. Crucially, when DNA damage is too severe or irreparable, the DDR can also trigger controlled cell fate decisions, such as apoptosis or senescence, to eliminate potentially hazardous cells and prevent the propagation of genomic errors (Chatzidoukaki et al., 2020, Roos et al., 2016, Xhemalçe et al., 2024). Thus, DDR has garnered immense interest as a hot subject to decipher the detailed molecular mechanisms driving tumorigenesis (Groelly et al., 2023, O'Connor, 2015). Defects in DDR-related genes (DRGs) and the resulting genomic instability are relevant to HNSCC oncogenesis and prognosis. For instance, mutations in the DDR pathway including those in BRCA2, ARID1A, ATM, and BRCA1 are prevalent in HNSCC (Papalouka et al., 2023, Wei et al., 2023). These genetic alterations significantly correlated with overall survival rates in those affected patients (Burcher et al., 2021). In addition, the DDR-related pathway has been reported to be vital for the treatment response of HNSCC. Preclinical and clinical studies have suggested that therapeutic targeting of DDR-related genes using small molecular inhibitors (PPAR/ATM/ATR/WEE1 inhibitors) alone or combined with radiotherapy or chemotherapy has shown substantial anti-cancer effects against HNSCC and held tremendous clinical potentials (Molkentine et al., 2021, Moutafi et al., 2021, Papalouka et al., 2023).

With the rapid advancement of high-throughput sequencing and sophisticated bioinformatics algorithms, various DDR-related prognostic signatures have been established with remarkable effectiveness and translational potential across multiple carcinomas (Li et al., 2023, Li et al., 2024, Xu et al., 2023). However, the detailed associations between DDR and HNSCC development are still underexplored. Due to the critical role of DDR during HNSCC tumorigenesis, progression, and treatment response, herein we intended to develop a novel DRG-based prognostic signatures for HNSCC via a comprehensive bioinformatics approach. A DDR-related gene of interest was selected and further experimentally validated via a pharmacological inhibition assay in vitro.