Systemic Lipid Peroxidation and Colorectal Cancer Risk: A Time-Varying Relationship

Despite widespread interest, large randomized controlled trials have failed to demonstrate chemopreventive benefits of antioxidant supplementation, raising concerns about its efficacy and safety. Building on our prior observation of a time-dependent inverse association between systemic oxidative stress (OxS), assessed using nucleic acid oxidation biomarkers, and colorectal cancer (CRC) risk, we extended this investigation to systemic lipid peroxidation and evaluated whether a composite OxS index incorporating DNA, RNA, and lipid markers improves risk characterization. We conducted a nested case-control study within two Shanghai cohorts (1938 CRC cases) and replicated findings in a US cohort (285 cases). Systemic lipid peroxidation was assessed using urinary F₂-isoprostanes (F₂-IsoPs), quantified by UPLC-MS/MS. Conditional logistic regression estimated odds ratios (ORs) for CRC risk. Lower levels of 5-F_2t-IsoP, a major F₂-IsoP isomer generated exclusively via free radical oxidation, were associated with increased CRC risk in both the primary and replication cohorts. Time-dependent associations were evaluated in the Shanghai cohorts. For CRC diagnosed within 5 years following enrollment, multivariable-adjusted ORs (95% CI) at the 10th and 90th percentiles of 5-F_2t-IsoP levels, relative to the median, were 1.57 (1.26-1.96) and 0.61 (0.42-0.89), respectively, indicating a 2.2-fold difference in risk. The composite OxS index showed an even stronger association (3.9-fold difference). No significant associations were observed for diagnoses beyond 5 years. This study provides new evidence that systemic OxS is inversely and time-dependently associated with CRC risk during later stages of disease development, raising concerns that lowering systemic OxS via high-dose antioxidant supplementation potentially carry unintended risks for high-risk individuals.