LAUSR

Metastasis remains the leading cause of cancer‐related mortality, yet effective interventions against KRASG12C/D driven lung adenocarcinoma metastasis ared limited. In this study, using KRASG12D/–;TP53–/–;COA4–/– transgenic mice, clinical specimens, organoid models, RNA sequencing, xenograft assays, and Seahorse metabolic profiling are employed to identify COA4 as an evolutionarily conserved regulator of cytochrome c oxidase (COX) and activator of CDC42. COA4 is found to be highly overexpressed in KRAS mutant tumors, correlating with increased metastatic burden and poor prognosis. Notably, COA4 deficiency markedly reduces lymph node metastasis. Mechanistically, KRASG12C/D upregulates COA4 via PI3K signaling and E2F1‐mediated transcriptional activation. Functionally, COA4 overexpression enhances transendothelial migration, extravasation, metastatic colonization, and organoid formation in vitro and in vivo, while its knockdown reverses KRAS‐driven metastasis without affecting proliferation. Subcellular fractionation reveals that mitochondrial COA4 augments COX activity to drive oxidative phosphorylation, while cytosolic COA4 binds and activates CDC42 to regulate pseudopodia formation. Pharmacological blockade of COX, oxidative phosphorylation, or CDC42 effectively suppressed COA4‐driven metastasis, with combination treatments yielding synergistic inhibition. Remarkably, the Saccharomyces cerevisiae COA4 ortholog recapitulates these dual functions, underscoring their evolutionary conservation. These findings establish COA4 as a critical KRASG12C/D effector governing metastasis through dual COX‐CDC42 modulation, highlighting its therapeutic potential for KRASG12C/D‐driven malignancies.