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A proteogenomic analysis combining genomics, transcriptomics, proteomics, and phosphoproteomics is performed on 102 samples from 34 treatment\u2010na\u00efve CRLM patients, including primary CRC, adjacent normal colorectal, and matched liver metastasis tissues. CRC cell lines, organoids, mouse models, and an independent patient cohort are used to validate the findings. Proteomics and phosphoproteomics show profoundly dysregulated pathways in liver metastasis tissues, notably disruptions in carbon metabolism. Functional validation using CRC organoids and mouse models demonstrates that the one\u2010carbon metabolism enzyme SHMT1 promotes CRC tumorigenesis and metastasis via formate\u2010mediated AMPK inhibition, whereas PIM kinase\u2010dependent NDRG1 Ser330 phosphorylation exacerbates liver metastasis by promoting ubiquitin\u2010dependent degradation of NDRG1. 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