Sphingolipid Remodeling in Colorectal Cancer Reveals a Continuum-like Metabolic Organization

Colorectal cancer (CRC) exhibits substantial metabolic heterogeneity, but the organization of sphingolipid remodeling remains incompletely understood. In this exploratory single-center study, we integrated patient-matched tissue lipidomics, systemic oxidative stress profiling, and independent transcriptomic analyses. Tumor tissue, adjacent non-neoplastic mucosa, and preoperative serum were collected from 40 patients with CRC, with serum obtained from 23 hospitalized non-cancer controls. Sphingolipids were quantified by UHPLC-MS/MS, while total antioxidant capacity, total oxidant status, and oxidative stress index characterized systemic redox status. Paired lipidomics revealed coordinated remodeling with increased S1P-associated measures, selective ceramide depletion, and elevated S1P-to-ceramide ratios. Multivariate analyses did not identify stable discrete lipidomic subgroups and revealed variation consistent with a continuum-like organization within the measured sphingolipid feature space. In separate principal component analyses, ratio-derived variables showed a more concentrated low-dimensional covariance structure than absolute lipid concentrations. Circulating sphingolipids showed limited correspondence with tumor-local remodeling, whereas oxidative stress markers showed strong apparent discrimination between CRC and hospitalized non-cancer controls, although this finding may be affected by residual confounding. TCGA-GTEx analyses provided complementary pathway-level transcriptomic context, while anatomically resolved analysis of 374 TCGA tumors identified 3376 genes significantly associated with colorectal anatomical position, including six sphingolipid-related genes. Overall, these exploratory findings support a conceptual CRC Metabolic Continuum while requiring validation in larger, independent cohorts.