Consistent Metabolomic and Genetic Evidence Validates Acisoga as a Key Contributor to Colorectal Neoplasia Progression

Background: Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality worldwide. Early detection and accurate risk stratification of precursor lesions remain critical challenges. Integrating metabolomics with genetic analysis may improve understanding of CRC development and identify disease determinants . Methods: Untargeted serum metabolomics was performed in 513 individuals: 185 controls, 74 low-, 98 intermediate-, and 100 high-risk lesions , and 56 CRC cases. Overall, 1,562 metabolic features were analysed using linear trend models with multiple-testing correction. Significant metabolites were further investigated through metabolite-level genome-wide association studies (GWAS). Findings were externally validated in 1,121 CRC-control pairs from The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in CRC GWAS meta-analysis. Results: The polyamine Acisoga, showed statistically significant increasing trends across CRC progression (p=2.8×10-5). The association was independently validated in EPIC (OR=1.23, 95% CI: 1.01–1.50). Metabolite-level GWAS identified genome-wide significant loci, including OPCML, EWSAT1, and CMKLR1. Genetically predicted Acisoga levels were positively associated with CRC risk (p=0.003), with consistent results in sensitivity analyses using previously reported Acisoga-associated variants. Conclusions: We demonstrate a reproducible association between Acisoga and CRC progression and risk, supported by metabolomic, genetic, and external data. This integrative approach advances understanding of metabolic processes involved in CRC and supports further evaluation of Acisoga in risk research. Impact: This work supports Acisoga as a potential circulating biomarker for colorectal cancer risk, with implications for early detection and prevention in screening populations.