Novel cuproptosis-related genes <i>C1QBP</i> and <i>PFKP</i> identified as prognostic and therapeutic targets in lung adenocarcinoma

Excessive intracellular copper accumulation triggers cuproptosis, a novel regulated cell death process with therapeutic potential. Analyzing 566 The Cancer Genome Atlas samples alongside lung adenocarcinoma (LUAD)-specific microarray and single-cell sequencing data, we identified 109 cuproptosis-associated genes, of which <i>C1QBP</i> and <i>PFKP</i> emerged as key prognostic markers. Four-gene risk model stratified patients into high- and low-risk groups with distinct survival outcomes, where high-risk scores correlated with advanced TNM stages. Clinical validation confirmed that elevated <i>C1QBP</i>/<i>PFKP</i> expression in LUAD tissues predicted shorter progression-free survival. Functional assays demonstrated that silencing <i>C1QBP</i> or <i>PFKP</i> increased intracellular copper concentration, suppressed proliferation, and inhibited invasion, mechanistically linking these genes to cuproptosis dysregulation. Our findings nominate <i>C1QBP</i>/<i>PFKP</i> as actionable targets for LUAD therapy, offering both prognostic biomarkers and copper-metabolism-directed treatment strategies.