Abstract The objective of this research was to create a prognostic model focused on genes related to ubiquitination (UbRGs) for evaluating their clinical significance in head and neck squamous cell carcinoma (HNSCC) patients. The transcriptome expression data of UbRGs were obtained from The Cancer Genome Atlas (TCGA) database, and weighted gene co-expression network analysis (WGCNA) was used to identify specific UbRGs within survival-related hub modules. A multi-gene signature was formulated using LASSO Cox regression analysis. Furthermore, various analyses, including time-related receiver operating characteristics (ROCs), Kaplan–Meier, Cox regression, nomogram prediction, gene set enrichment, co-expression, immune, tumor mutation burden (TMB), and drug sensitivity, were conducted. Ultimately, a prognostic signature consisting of 11 gene pairs for HNSCC was established. The Kaplan–Meier curves indicated significantly improved overall survival (OS) in the low-risk group compared to the high-risk group (p < 0.001), suggesting its potential as an independent and dependable prognostic factor. Additionally, a nomogram with AUC values of 0.744, 0.852, and 0.861 at 1-, 3-, and 5-year intervals was developed. Infiltration of M2 macrophages was higher in the high-risk group, and the TMB was notably elevated compared to the low-risk group. Several chemotherapy drugs targeting UbRGs were recommended for low-risk and high-risk patients, respectively. The prognostic signature derived from UbRGs can effectively predict prognosis and provide new personalized therapeutic targets for HNSCC. Keywords: ubiquitination-related gene, head and neck squamous cell carcinoma, TCGA, bioinformatics analysis, prognosis 1. Introduction Head and neck cancer is a lethal malignancy, ranking among the top ten most prevalent tumors in both men and women worldwide. The year 2020 witnessed a number of new cases at 931,922 and 467,125 fatalities [[34]1,[35]2]. In the United States alone, there were approximately 136,550 newly diagnosed cases and a death toll of around 35,000 [[36]3]. Head and neck squamous cell carcinoma (HNSCC) stands as the predominant type within this category, constituting more than 90% of all head and neck cancers [[37]4]. Recent years have seen remarkable progress in targeted therapy alongside the emergence of immunotherapy as an innovative treatment modality [[38]5,[39]6,[40]7]. Although targeted immunotherapy has shown enhanced patient survival rates in HNSCC, the proportion of patients who exhibit a lasting response to these treatments is limited to only 15–20% [[41]8]. Even though patients with locoregionally advanced HNSCC are treated with surgery, radiotherapy, chemotherapy, immunotherapy, or combination therapy, the five-year overall survival (OS) rate remains suboptimal [[42]9]. Therefore, it is essential to discover dependable diagnostic indicators and to pinpoint new intervention targets and prognosis factors. Ubiquitination, a reversible and dynamic post-translational modification, is a crucial regulator of cellular protein degradation pathways [[43]10,[44]11]. The ubiquitination pathway entails the conjugation of ubiquitin molecules to the target protein, followed by its recognition and subsequent degradation mediated by proteasomes [[45]12]. In human cells, more than 80% of protein is degraded through the ubiquitination enzyme pathway [[46]13]. Ubiquitination not only affects the protein localization, metabolism, function, regulation and degradation [[47]14], but it also regulates various cellular processes such as cell cycle, proliferation, apoptosis [[48]15,[49]16], differentiation, inflammation, and immune response [[50]17,[51]18]. The organism’s health cannot be separated from the harmonious equilibrium between the ubiquitination and deubiquitination of intracellular proteins, which dynamically adjusts in response to physiological demands. A growing body of reports suggests that abnormal control of the ubiquitination pathway could lead to various diseases, including malignancies and autoimmune disorders [[52]19,[53]20,[54]21,[55]22]. For instance, the E3 ubiquitin ligase HRD1 promotes lung cancer through ubiquitination of the Sirtuin 2 protein [[56]23]. The elevated expression of Cullin1, a pivotal scaffold protein in the ubiquitin E3 ligase complex, was significantly correlated with inferior overall survival and lymph node metastasis in gastric cancer [[57]24]. Therefore, investigating the dysregulated ubiquitin system as a promising therapeutic target for these diseases holds significant scientific and clinical implications. Precision-targeted ubiquitination and degradation of oncogene proteins offer bright prospects for drug development in cancer. In addition, molecular subtyping and risk stratification tools could be developed for prognostic prediction using ubiquitination-related genes (UbRGs) [[58]25]. However, few studies have been conducted to determine whether there is a correlation between ubiquitination and the outcome assessment of HNSCC. The ubiquitin proteasome system is essential for protein degradation and is associated with oncogenesis. Therefore, our aim was to investigate the involvement of all known UbRGs in HNSCC. Utilizing the TCGA dataset, we screened for UbRGs associated with outcomes in HNSCC patients using various statistical strategies. The main contributions of this work are as follows: (1) we established a novel and reliable risk score model based on these screened UbRGs, which can be employed to predict the prognosis of HNSCC patients; (2) based on this risk model, we developed a nomogram for individualized prognosis assessment to assist clinicians in making prognostic judgments for individual patients; (3) additionally, we characterized the immune landscape of HNSCC patients in relation to the prognostic risk model, providing valuable references for future studies on HNSCC immunization. In the