Integrative Multi-Omics Analysis Reveals the Molecular Characteristics, Tumor Microenvironment, and Clinical Significance of Ubiquitination Mechanisms in Lung Adenocarcinoma.

Ubiquitination is a dynamic and reversible post-translational modification mediated by ubiquitination regulators (UBRs), which plays an essential role in protein stability, cell differentiation and immunity. Dysregulation of UBRs can lead to destabilization of biological processes and may induce serious human diseases, including cancer. Many UBRs, such as E3 ubiquitin ligases and deubiquitinases (DUBs), have been identified as potential drug targets for cancer therapy. However, the potential clinical value of UBRs in lung adenocarcinoma (LUAD) remains to be elucidated. Here, we identified 17 hub UBRs from high-confidence protein-protein interaction networks of UBRs correlated with cancer hallmark-related pathways using four topological algorithms. The expression of hub UBRs is affected by copy number variation and post-transcriptional regulation, and their high expression is often detrimental to patient survival. Based on the expression profiles of hub UBRs, patients can be classified into two ubiquitination subtypes with different characteristics. These subtypes exhibit significant differences across multiple dimensions, including survival, expression level, mutation burden, female predominance, infiltration level, immune profile, and drug response. In addition, we established a scoring system for evaluating the ubiquitination status of individual LUAD patients, called the ubiquitination-related risk (UB_risk) score, and found that patients with low scores are more likely to gain advantages from immunotherapy. The results of this study emphasize the critical role of ubiquitination in the classification, tumor microenvironment and immunotherapy of LUAD. The construction of the UB_risk scoring system lays a research foundation for evaluating the ubiquitination status of individual LUAD patients and formulating precise treatment strategies from the ubiquitination level.