Sex-based differences in circulating microRNA and metabolite signatures associated with physical activity in Lynch Syndrome carriers

Lynch syndrome carriers face a high cancer risk, especially for colorectal cancer. Although physical activity is known to lower cancer risk in Lynch syndrome, it remains unclear whether this protective effect is the same between sexes. We used an integrated omics approach to examine molecular mechanisms associated with physical activity in Lynch syndrome, focusing on sex-specific differences and connections to cancer-related processes. We combined miRNomics and metabolomics data from serum samples with questionnaire-based physical activity-level assessment. Bioinformatics approaches identified molecular mechanisms associated with physical activity. We observed sex-based differences in physical activity-associated circulating microRNAs and metabolites. In females, physical activity was linked to lipid metabolism. In males, microRNAs negatively associated with physical activity were overrepresented in distinct cancers, regulating pathways involved in cell growth, apoptosis, transcription, senescence, and the cell cycle. Four physical activity-associated microRNAs ( hsa-miR-885-3p , hsa-miR-483-5p , hsa-miR-374a-5p , hsa-miR-301a-3p ) strongly correlated with metabolites related to lipid and fatty acid metabolism and inflammation, with correlation patterns differing by sex. Expression of these microRNAs changed after acute exercise. Our findings highlight the importance of considering sex as a biological factor in physical activity-based cancer prevention strategies for Lynch syndrome and provide novel insights into molecular mechanisms for cancer prevention.