Integrated functional and metabolomic profiling reveals coordinated roles of CDK1 and FUT2 in lung adenocarcinoma progression

Lung adenocarcinoma (LUAD) exhibits uncontrolled proliferation and metabolic reprogramming. Cyclin-dependent kinase 1 (CDK1) drives the G2/M transition, while fucosyltransferase 2 (FUT2) catalyzes α1,2-fucosylation, which broadly influences receptor signaling and stress responses. The mechanism by which these two proteins interact to shape LUAD metabolism remains unclear. We employed structural modeling, transcriptomics, functional assays, and untargeted metabolomics to elucidate the roles of CDK1 and FUT2 in LUAD. A549 cells, a well-characterized lung adenocarcinoma model commonly used for studies of proliferation and metabolic rewiring, were selected for functional assays and untargeted metabolomics. Overexpressing CDK1 or FUT2 in A549 cells significantly altered cell viability and induced distinct metabolic shifts. CDK1 overexpression was associated with enrichment of oxidative phosphorylation and AMPK signaling pathways, thereby elevating key metabolites such as NAD + and taurocholic acid. FUT2 overexpression perturbed tryptophan metabolism and Wnt signaling, resulting in increased levels of L-kynurenine, pyridoxine, and xanthurenic acid. Functionally, CDK1 inhibition using RO-3306 suppressed A549 cell proliferation and disrupted energy metabolism, whereas FUT2 promoted proliferation, potentially through antioxidant defense and lipid biosynthesis pathways. CDK1 and FUT2 regulate complementary metabolic programs in LUAD, linking cell-cycle control and glycosylation to metabolic adaptation. These results provide a rationale for combined targeting of CDK1- and FUT2-linked pathways and support further preclinical evaluation of combination regimens.