Papadimitriou, NikosKazmi, NabilaTsilidis, Konstantinos K.Richmond, Rebecca C.Lynch, Brigid M.Bendinelli, BenedettaRicceri, FulvioSánchez Pérez, María JoséTrobajo-sanmartin, CaminoJakszyn, PaulaSimeon, VittorioSeveri, GianlucaPerduca, VittorioTruong, ThérèseFerrari, PietroKeski-Rahkonen, PekkaWeiderpass, ElisabeteEichelmann, FabianSchulze, Matthias B.Katzke, VerenaFortner, Renée T.Heath, Alicia K.Aune, DagfinnHarewood, RheaDahm, Christina C.Aginagalde Llorente, Adrian HugoGunter, Marc J.Murphy, NeilLewis, Sarah J.2025-06-172025-06-172025-01-301538-7755https://hdl.handle.net/2445/221595Background: Current evidence suggests higher physical activity (PA) levels are associated with a reduced risk of colorectal cancer. However, the mediating role of the circulating metabolome in this relationship remains unclear.Methods: Targeted metabolomics data from 6,055 participants in the European Prospective Investigation into Cancer and Nutrition cohort were used to identify metabolites associated with PA and derive a metabolomic signature of PA levels. PA levels were estimated using the validated Cambridge PA index based on baseline questionnaires. Mediation analyses were conducted in a nested case-control study (1,585 cases, 1,585 controls) to examine whether individual metabolites and the metabolomic signature mediated the PA-colorectal cancer association.Results: PA was inversely associated with colorectal cancer risk (OR per category change: 0.90, 95% confidence interval, 0.83-0.97; P value = 0.009). PA levels were associated with 24 circulating metabolites after FDR correction, with the strongest associations observed for phosphatidylcholine acyl-alkyl (PC ae) C34:3 (FDR-adjusted P value = 1.18 x 10-10) and lysophosphatidylcholine acyl C18:2 (FDR-adjusted P value = 1.35 x 10-6). PC ae C34:3 partially mediated the PA-colorectal cancer association (natural indirect effect: 0.991, 95% confidence interval, 0.982-0.999; P value = 0.04), explaining 7.4% of the association. No mediation effects were observed for the remaining metabolites or the overall PA metabolite signature.Conclusions: PC ae C34:3 mediates part of the PA-colorectal cancer inverse association, but further studies with improved PA measures and extended metabolomic panels are needed.Impact: These findings provide insights into PA-related biological mechanisms influencing colorectal cancer risk and suggest potential targets for cancer prevention interventions.10 p.application/pdfengcc-by-nc-nd (c) Papadimitriou et al., 2025http://creativecommons.org/licenses/by-nc-nd/3.0/es/Càncer colorectalMetabolòmicaColorectal cancerMetabolomicsinfo:eu-repo/semantics/article2025-06-10info:eu-repo/semantics/openAccess39883068