Serum miRNA and Metabolomic Signatures of Residential Radon Exposure in Chiang Mai, Thailand

Residential radon is a leading environmental cause of lung cancer, but circulating biomarkers linking home exposure to pathogenic biology are not well defined. We conducted an exposure-contrast study in Hang Dong District, Chiang Mai, measuring indoor radon in 48 homes and enrolling adults from <50 Bq/m³ (low) and ≥100 Bq/m³ (high) households for serum profiling. Mean indoor radon was 61.8 ± 18.4 Bq/m³ (range 34-126), with 6.2% of homes ≥100 Bq/m³. Small RNA sequencing identified 55 differentially expressed miRNAs (12 up, 43 down) in high-radon serum. Notably, miR-200b-3p, miR-200c-3p, and miR-194-5p were increased, while miR-3913-5p, miR-584-5p, miR-30a-3p, miR-22-3p, and miR-125a-5p were decreased. Target enrichment (KEGG/GO) implicated PI3K-Akt and MAPK hubs with Ras/Wnt/VEGF alongside focal adhesion/ECM-receptor/actin-cytoskeleton and immune-regulatory modules. Untargeted LC-MS metabolomics showed exposure-aligned shifts: higher PUFAs and oxylipins (e.g., AA, EPA; 9-HEPE, 8-HETE, 5,12-DiHETE), elevated acyl-carnitines (β-oxidation), and increased inosine/hypoxanthine, consistent with lipid/steroid remodeling, mitochondrial fuel reprogramming, oxidative stress, and nucleotide turnover. Integrated interpretation supports DDR/ATM → PI3K/Akt-MAPK activation with EMT/adhesion remodeling, angiogenic signaling, and immune modulation-linking residential radon to lung cancer mechanisms. Given the small sample size (<i>n</i> = 10), these findings should be interpreted as preliminary and hypothesis-generating, warranting validation in larger cohorts. Nevertheless, findings support household testing, remediation at ≥100 Bq/m³, and integrated exposure studies considering PM2.5 co-exposures.