Abstract Background The relationship between metabolic syndrome (MetS) and colorectal cancer (CRC) remains incompletely understood, with chronic inflammation hypothesized as a potential mediator. This study aimed to investigate associations among MetS, systemic inflammation biomarkers, and CRC risk, while focusing on the mediating role of inflammation. Methods Using data from 335 544 participants in the UK Biobank, we assessed associations between MetS, CRC risk, and six systemic inflammation biomarkers neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and inflammatory burden index (IBI). Fine and Gray’s competing risk model, multivariable linear regression, and Cox proportional hazards models were employed. Causal mediation analysis was used to evaluate the mediating effects of inflammation biomarkers. Results MetS was associated with increased CRC risk (HR = 1.11, 95% CI = 1.03–1.20, P = .007), with central obesity and hyperglycemia showing the strongest associations. Five inflammation biomarkers (NLR, PLR, SII, SIRI, and IBI) were positively associated with both MetS and CRC risk. Mediation analysis revealed that these biomarkers partially mediated the MetS–CRC relationship, with IBI accounting for the largest mediating effects (16.6%). Conclusion This study confirms that both MetS and systemic inflammation contribute to increased CRC risk, with inflammation playing a significant mediating role. These findings provide novel insights into underlying mechanisms and highlight the potential of inflammation biomarkers, particularly IBI, for improving early CRC risk prediction in individuals with metabolic dysfunction. Key messages What is already known on this topic: Metabolic syndrome (MetS) is associated with an increased colorectal cancer (CRC) risk, but the biological pathway remains incompletely understood. Systemic low-grade inflammation has been proposed as a mediator, yet composite inflammation indices are underexplored. What this study adds: In 335 544 UK Biobank participants, MetS was associated with a higher risk of CRC (HR = 1.11, 95% CI 1.03–1.20). Five systemic inflammation biomarkers (NLR, PLR, SII, SIRI, and IBI) were associated with both MetS and CRC. Mediation analysis indicated partial mediation, with IBI contributing the largest proportion (16.6%). How this study might affect research, practice, or policy: Incorporating systemic inflammation indices, particularly IBI, may improve early risk stratification for CRC among individuals with MetS. These findings support the development of prevention strategies targeting low-grade inflammation, while guiding future mechanistic and translational research.
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