Childhood obesity may induce epigenetic changes, affecting long-term cardiac health. However, empirical evidence remains scarce. Leveraging the prospective cohort of Beijing Child and Adolescent Metabolic Syndrome study (BCAMS), we investigated the blood DNA methylation signatures associated with childhood obesity and the future risk of cardiac hypertrophy in young adults, confirming causality with Mendelian randomization (MR). The BCAMS study followed children into adulthood. Data including blood DNA methylation profiles, along with lifestyles, blood levels of 7 adipokines and 32 amino acids were collected at baseline. Echocardiographic measurements were assessed at the 10-year follow-up. Enrichment and correlation analyses were performed, and two-sample MR analyses involving 105,268 participants from European biobanks were employed to infer causality. Cross-sectionally, we identified 376 differentially methylated sites between children with obesity and normal-weight controls (n=25), particularly within genes enriched in the cardiomyopathy pathway. Longitudinally, 11 childhood obesity-associated methylation sites, especially cg25835058 (KAZN), cg01362389 (TDH) and cg12099423 (SLC17A9), showed strong correlations with left ventricular index (LVMI) at the 10-year follow-up (P<.0017). Additionally, these sites were associated with traditional risk factors, notably glutamine, which displayed strongest protective association with LVMI (-1.72g/m2.7 per 1SD increase, P<.001) when validated with the entire cohort (n=326). MR analysis confirmed the significant correlation between cg12099423 methylation levels and SLC17A9 expression, and the causality between gene expression levels (KAZN, TDH, SLC17A9) and LVMI. Methylation associated with childhood obesity, particularly SLC17A9, may function as an epigenetic mechanism impacting long-term cardiac health later in life, emphasizing the significance of early intervention.Copyright © 2025 Elsevier Inc. All rights reserved.