Background/Aims: Colorectal cancer (CRC), the second leading cause of cancer-related deaths worldwide, remains a major clinical challenge due to chemoresistance and metastatic progression. Platinum-based regimens such as FOLFOX are standard frontline therapies, yet their long-term efficacy is limited. Tumor metabolism has emerged as a key mediator of therapeutic response, but patient-specific metabolic vulnerabilities are still underexploited. We aimed to identify novel metabolic targets that could enhance FOLFOX efficacy in CRC using a systems biology approach.

Analysis: Multi-omics analyses were performed in eight CRC cell lines treated and untreated with FOLFOX, including transcriptomics (RNAseq), targeted metabolomics (Absolute IDQ p180 kit, Biocrates), and exchange fluxes (glucose, lactate, amino acids, biogenic amines, oxygen, proton). These datasets were integrated into contextualized Genome-Scale Metabolic Models (GEMs) reconstructed with the CORDA algorithm, enabling subtype-specific metabolic networks. Models were subsequently coupled with flux balance analysis. Our approach revealed how CRC cells rewire central metabolism to evade FOLFOX cytotoxicity. Distinct subtype-specific metabolic rewiring patterns were identified, each associated with differential drug response. Importantly, we uncovered novel synthetic-lethal targets whose inhibition could potentiate FOLFOX efficacy. CORDA further demonstrated unique capacity to pinpoint patient-specific metabolic vulnerabilities, highlighting its translational potential. This framework advances precision oncology by transforming multi-omics data into actionable therapeutic strategies. By moving beyond static biomarker discovery, we propose a dynamic, model-driven approach to overcome chemoresistance and improve outcomes in CRC and other solid tumors.