Background <p>Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder characterized by recurrent episodes of intermittent hypoxia (IH) and sleep fragmentation. OSA is strongly associated with cardiometabolic morbidities, many of which correlate with the severity of IH. While the genetic basis of OSA remains unclear, epigenetic modifications, particularly DNA methylation, have emerged as key contributors to its pathophysiology.</p> Methods <p>In this pooled analysis, we systematically examined publicly available DNA methylation datasets from OSA patients and murine IH models to identify common methylation signatures at both the single-gene and pathway levels.</p> Results <p>We found 720 differentially methylated genes in human OSA, suggesting a regulatory role of DNA methylation in OSA-associated cardiometabolic dysfunction. While the specific differentially methylated genes differed between human OSA and murine IH models, there were notable similarities. In contrast, there was substantial overlap between the human and animal data at the pathway level. Most notably, differential methylation affected oxidative stress, inflammation, lipid metabolism, and PI3-AKT signaling pathways.</p> Conclusions <p>These findings provide further evidence that epigenetic mechanisms, particularly DNA methylation, mediate the systemic effects of OSA and IH. Our study underscores the need for targeted research to elucidate the causal role of these epigenetic changes and their potential reversibility through therapeutic interventions.</p>