The systematic analysis of genes related to butyrate metabolism suggests that CDKN3 could serve as a promising therapeutic target for lung adenocarcinoma treatment.

Background: Metabolic pathways are known to significantly impact the development and advancement of lung cancer. This study sought to establish a signature related to butyrate metabolism that is specifically linked to lung adenocarcinoma (LUAD).

Methods: For the purpose of identifying butyrate metabolism-related differentially expressed genes (BMR-DEGs) in the TCGA-LUAD dataset, we introduced transcriptome data. This was followed by the implementation of the univariate Cox and LASSO analyses in order to construct a LUAD gene signature. We performed a comprehensive analysis of gene function enrichment between the two populations at risk, thoroughly examined their immune microenvironment characteristics, and assessed the effectiveness of immunotherapy. Finally, the function of CDKN3 in LUAD was verified by in vitro experiments.

Results: Through a comprehensive analysis of the TCGA-LUAD dataset, 51 significant BMR-DEGs were confirmed. Subsequently, five characteristic genes, CPS1, ABCC2, CDKN3, SLC2A1, and IGFBP1 were identified to create prognostic features for butyrate metabolism related outcomes in LUAD. Cox regression analysis determined that the pathological T stage, tumor stage, and RiskScore could serve as independent prognostic indicators. Analysis of the abundance of 22 immune infiltrating cells revealed that 15 immune cell types exhibited substantial differences and were strongly associated with risk ratings and prognosis. An important correlation exists between risk ratings and immunological checkpoints, which can be utilized to forecast the efficacy of treatment. In the high-risk group, there was an upregulation of the expression of PD-L2, PD-L1, and PD-1. Additionally, the risk score showed a positive correlation with TIDE and Exclusion score, while showing a negative correlation with Dysfunction score. Furthermore, the IC₅₀ values for cisplatin, paclitaxel, and docetaxel were notably elevated in the high-risk group, indicating that these medications could potentially provide therapeutic advantages for this particular group. Finally, we determined that knockdown CDKN3 inhibited the proliferation and metastasis of LUAD cells.

Conclusion: We identify and validate a novel BMR-related prognostic signature comprising 5 DEGs for LUAD patients. Our data might provide a new molecular target for LUAD treatment.