The molecular key in exercise-induced lung cancer prevention: insights from Mendelian randomization and...

Lung cancer is a leading cause of cancer-related mortality globally, yet its association with physical exercise remains incompletely understood. This study employed Mendelian randomization (MR) and bioinformatics to investigate the causal link between physical exercise and lung cancer, further validating potential molecular mediators through experimental analysis.

We applied a two-sample MR framework, using genetic variants as instrumental variables, to examine the causal associations between five distinct exercise modalities-recreational walking, strenuous sports, miscellaneous activities, light do-it-yourself (DIY) activities, and heavy DIY activities-and lung cancer risk. This analysis was conducted using data from the UK Biobank and the Genome-Wide Association Studies (GWAS) consortia. To ensure the robustness of our results, we performed sensitivity analyses including MR-Egger, weighted median, and MR-PRESSO. Furthermore, we investigated potential mediators such as lipids, immune cells, inflammatory cytokines, and metabolites through MR. Bioinformatics analyses, specifically GEPIA, were employed to identify candidate genes and key molecules, and the expression level of the key molecule SULT1A1 was further validated by Qpcr, Western blot and immunofluorescence.

The findings indicated that participation in activities such as swimming, cycling, fitness training, bowling (ebi-a-GCST90018875: P = 0.017, OR = 0.086;ieu-b-4954: P = 0.004, OR = 0.972; ieu-b-4955: P = 0.003, OR = 0.972), and walking (ebi-a-GCST90018875: P = 0.021, OR = 0.170; ieu-b-4954, P = 0.025, OR = 0.980; ieu-b-4955: P = 0.016, OR = 0.978) was associated with a decreased risk of lung cancer. Our analysis found significant causal relationships between lung cancer and 21 lipids, 7 immune cell subtypes, 4 inflammatory markers, and 16 metabolites, but no statistically significant regulatory effect of physical activity on them. Bioinformatics analysis revealed that SULT1A1 expression was significantly lower in lung tumors, specifically in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and was correlated with improved prognosis (hazard ratio [HR] = 0.67 for LUAD, P = 0.0083). In murine models, exercise led to a reduction in tumor growth, volume, and Ki-67 + cell proliferation, while concurrently increasing SULT1A1 mRNA and protein expression levels (P < 0.05).

This study offers causal evidence supporting the protective effects of exercise against lung cancer, potentially through pathways dependent on SULT1A1.