Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths. Integrating cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present a comparative mRNA-seq analysis of tissue samples from 32 CRC patients, pairing tumors with adjacent healthy tissues. Differential expression gene (DEG) analysis revealed dysregulated metabolic programs. We focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2, which compose the cystine/glutamate transporter (Xc-) system. To assess the oncogenic potential of the Xc- system, we analyzed gene perturbations from CRISPR screens across various cell types and used functional assays in five primary patient-derived organoid models. We identified a previously uncharacterized cell surface protein signature predicting chemotherapy resistance and highlighted the causality and potential of pharmacological blockage of ferroptosis as a promising avenue for cancer therapy. Redox homeostasis, ion/amino acid transporters, and regulators of neuronal survival and differentiation were pathways associated with these co-dependent genes in patient specimens. This study highlights several potential clinical targets for CRC therapy and promotes the use of patient-derived organoids oids to functionally validate in silico predictions.