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Building on our prior observation of a time\u2010dependent 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\u2013control study within two Shanghai cohorts (1938 CRC cases) and replicated findings in a US cohort (285 cases). Systemic lipid peroxidation was assessed using urinary F\n                    <jats:sub>2<\/jats:sub>\n                    \u2010isoprostanes (F\n                    <jats:sub>2<\/jats:sub>\n                    \u2010IsoPs), quantified by UPLC\u2010MS\/MS. Conditional logistic regression estimated odds ratios (ORs) for CRC risk. Lower levels of 5\u2010F\n                    <jats:sub>2t<\/jats:sub>\n                    \u2010IsoP, a major F\n                    <jats:sub>2<\/jats:sub>\n                    \u2010IsoP isomer generated exclusively via free radical oxidation, were associated with increased CRC risk in both the primary and replication cohorts. Time\u2010dependent associations were evaluated in the Shanghai cohorts. For CRC diagnosed within 5\u2009years following enrollment, multivariable\u2010adjusted ORs (95% CI) at the 10th and 90th percentiles of 5\u2010F\n                    <jats:sub>2t<\/jats:sub>\n                    \u2010IsoP levels, relative to the median, were 1.57 (1.26\u20131.96) and 0.61 (0.42\u20130.89), respectively, indicating a 2.2\u2010fold difference in risk. The composite OxS index showed an even stronger association (3.9\u2010fold difference). No significant associations were observed for diagnoses beyond 5\u2009years. This study provides new evidence that systemic OxS is inversely and time\u2010dependently associated with CRC risk during later stages of disease development, raising concerns that lowering systemic OxS via high\u2010dose antioxidant supplementation potentially carry unintended risks for high\u2010risk individuals.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70585","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:41:08Z","timestamp":1781584868000},"page":"2170-2183","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic Lipid Peroxidation and Colorectal Cancer Risk: A Time\u2010Varying Relationship"],"prefix":"10.1002","volume":"159","author":[{"given":"Gong","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Epidemiology, Department of Medicine Vanderbilt\u2010Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical 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