AbstractCuproptosis is a manner of cell death which is related to the homeostasis of copper ions in the cellular environment and is expected to open a new direction of anti-tumor therapy. However, the studies on cuproptosis and copper homeostasis in lung adenocarcinoma (LUAD) are still limited. In this study, we identified new cuproptosis and copper homeostasis related genes (CHRGs) which were effective in stratifying genotyping clusters with survival differences based on transcriptomic data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Weighted Gene Co-expression Network Analysis (WGCNA) further expands the screening boundary of CHRGs, and finally we established a 10-CHRGs-based prognostic signature using lasso-penalized cox regression method, which were validated in GSE30219. Comprehensive bioinformatics analysis revealed these genes are potential regulators of modulating immunotherapy efficacy, drug resistance, tumor microenvironment infiltration, and tumor mutation patterns. Lastly, the scRNA-seq datasets GSE183219 and GSE203360 offers the evidences that CHRGs signature are mainly distributed in cancer epithelial cells, real time quantitative polymerase chain reaction (RT-qPCR) also confirmed the differential expression of these genes between normal lung cell line and lung adenocarcinoma cell lines. Collectively, our findings revealed new cuproptosis and copper homeostasis related genotyping clusters and genes which may play important roles in predicting prognosis, influencing tumor microenvironment and drug efficacy in LUAD patients.