A Shift in the Plasma 7-Oxysterol Redox Axis in Colorectal Cancer

Background/Objectives: Colorectal cancer (CRC) involves metabolic reprogramming, including altered cholesterol handling and redox homeostasis. Oxysterols link lipid metabolism with redox and immune regulation, but whether defined oxysterol redox systems are perturbed in the circulation is unclear. One such system is the 7-ketocholesterol (7-KC)/7β-hydroxycholesterol (7β-OHC) couple, interconverted by 11β-hydroxysteroid dehydrogenases (HSD11B1 and HSD11B2). Methods: We combined targeted LC-MS/MS profiling of plasma (CRC, n = 6; controls, n = 20) and paired tumour-normal tissues (10 pairs) with TCGA COAD/READ transcriptomes (normal, n = 51; tumour, n = 624). Oxysterols were normalised to cholesterol. Rank-based statistics, effect sizes, leave-one-out resampling and Benjamini-Hochberg correction were applied. Results: CRC plasma showed elevated hydroxylated 7-oxysterols (7β-OHC, ~2-fold, q = 0.002; 7α,25-dihydroxycholesterol, ~2.1-fold, q = 0.001). The side-chain oxysterols 25-OHC and 27-OHC were unchanged. Median 7-KC was markedly lower in CRC, but the individual comparison was not statistically significant (q = 0.263) in the context of substantial heterogeneity among healthy controls. The 7-KC/7β-OHC ratio was reduced ~23-fold (log₂FC = -4.5, 95% CI -5.0 to -1.6; q = 0.001). This reduction reflects the individually non-significant decrease in 7-KC together with the independently significant increase in 7β-OHC. The shift was consistent across all CRC samples and robust to resampling. In contrast, paired tumour tissues were heterogeneous with no consistent change. TCGA tumours showed downregulation of oxysterol pathway genes, most prominently HSD11B2 (~5-fold), which oxidises 7β-OHC to 7-KC. Conclusions: CRC is associated with a selective shift in the plasma 7-oxysterol redox axis that is directionally consistent with HSD11B2 suppression in CRC transcriptomes, but not mirrored by steady-state tumour oxysterol levels. The 7-KC/7β-OHC ratio provides a measure of the balance between these biochemically linked circulating oxysterols. Given the small plasma cohort, these findings warrant validation in larger, prospectively matched cohorts before their broader or clinical significance can be established.