Unveiling a dual‑pathway prognostic model: Integrating T cell‑related and ubiquitination‑related genes in lung adenocarcinoma

The prognosis of lung adenocarcinoma (LUAD) is closely associated with T‑cell function and ubiquitination; however, the underlying mechanisms have remained elusive. Therefore, there is an urgent need to identify robust prognostic biomarkers. Using The Cancer Genome Atlas (n=515) and the Gene Expression Omnibus Series GSE31210 (n=226) datasets, an integrated differential expression analysis, weighted gene co‑expression network analysis, Cox regression and least absolute shrinkage and selection operator regression were performed to identify a prognostic signature. Based on an eight‑gene risk model, patients were stratified into high‑risk and low‑risk groups. The model was subsequently evaluated through immune infiltration analysis, drug sensitivity assessment and reverse transcription‑quantitative PCR (RT‑qPCR) validation. Although the RT‑qPCR validation cohort was relatively small (n=20), limiting statistical power, the observed expression trends were consistent with the bioinformatics findings. An eight‑gene signature comprising RNF180, MAP3K3, TRIM2, RNF125, RWDD3, RNF144B, KCTD5 and TRIM27 was identified. In the training cohort, the risk model achieved area under the curve values of >0.6 for 1‑, 3‑ and 5‑year survival and was successfully validated in the independent GSE31210 cohort. A nomogram incorporating the risk score and M stage showed potential clinical utility within a limited threshold probability range. The high‑risk group exhibited distinct immune infiltration patterns and significantly higher Tumour Immune Dysfunction and Exclusion scores. Drug sensitivity analysis identified 125 agents, including axitinib, with significantly different half‑maximal inhibitory concentration (IC₅₀) values between the two risk groups. Specifically, high‑risk patients exhibited higher IC₅₀ values for certain drugs, indicating lower sensitivity, whereas low‑risk patients were more likely to respond to these agents. RT‑qPCR analysis of an expanded cohort of 20 paired LUAD and adjacent normal tissues confirmed the differential expression of five key genes: KCTD5, MAP3K3, RNF144B, TRIM2 and TRIM27. In conclusion, this novel prognostic model integrating T cell‑related and ubiquitination‑related genes provides a potential tool for risk stratification and personalized treatment in LUAD. It may also help clinicians identify high‑risk patients who could benefit from closer follow‑up or targeted therapeutic strategies.