Ontology-level serum and tumor–margin lipid remodeling across colorectal cancer progression: a cross-sectional study

Colorectal cancer (CRC) progression involves extensive metabolic reprogramming, but stage-related lipid alterations across circulating and local tissue compartments remain incompletely characterized. This study aimed to map serum and paired tumor–margin ontology-level lipid signals associated with pathological CRC progression. A cross-sectional cohort of 122 patients with histologically confirmed CRC stages I–IV was analyzed. Untargeted lipidomic profiling of preoperative serum and paired tumor and adjacent margin tissues was performed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry in positive and negative ionization modes. Feature-level signals were aggregated by MS-DIAL lipid ontology. Serum ontologies were evaluated individually, whereas tissue models jointly included adjacent-margin background and the within-patient tumor-vs-margin difference. Ordinal proportional-odds models were used for TNM, T and N stages, and logistic regression for angioinvasion and neuroinvasion. Unadjusted and age- and sex-adjusted models were reported. P values were nominal without correction for multiple testing. Serum negative-ionization associations were predominantly inverse. Higher MMPE signal was associated with lower odds of a more advanced TNM category (adjusted OR = 0.73, 95% CI 0.55–0.98; nominal p = 0.034) and lower odds of a higher N stage (adjusted OR = 0.72, 95% CI 0.53–0.99; nominal p = 0.042). In positive ionization, TG-EST (adjusted OR = 1.45, 95% CI 1.06–1.96; nominal p = 0.018) and EtherTG (adjusted OR = 2.26, 95% CI 1.08–4.74; nominal p = 0.031) were associated with higher T stage, whereas BRSE was associated with higher TNM stage (adjusted OR = 1.45, 95% CI 1.05–2.00; nominal p = 0.024) and N stage (adjusted OR = 1.51, 95% CI 1.08–2.11; nominal p = 0.016). In tissue models, a higher tumor-vs-margin BileAcid signal was associated with more advanced TNM stage (adjusted OR = 1.70, 95% CI 1.05–2.75; nominal p = 0.031) and angioinvasion (adjusted OR = 1.99, 95% CI 1.13–3.52; nominal p = 0.018), whereas the Cer_EODS tumor-vs-margin signal was associated with higher T stage (adjusted OR = 1.65, 95% CI 1.14–2.40; nominal p = 0.008) and N stage (adjusted OR = 1.71, 95% CI 1.16–2.51; nominal p = 0.006). CRC progression was associated with heterogeneous and compartment-specific ontology-level lipid remodeling rather than a uniform lipid signature. These findings identify candidate serum and tissue lipid domains for targeted, species-resolved validation, but do not establish confirmatory biomarkers because of the exploratory design and absence of multiplicity correction. Not applicable.