Abstract
Complex chronic conditions represent a growing health burden that is poorly understood and inadequately managed within current health systems. This review focuses on the potential of epigenetic DNA methylation to provide a pathway for better understanding of four closely related conditions: myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), long COVID (LC), fibromyalgia (FM), and hypermobile Ehlers-Danlos syndrome (hEDS). These conditions have extensive overlapping symptoms, suggesting shared underlying pathophysiological mechanisms. Epigenetic regulation, particularly DNA methylation, provides a powerful framework for comparative and longitudinal studies across these clinically overlapping conditions. Here, we synthesise evidence from current DNA methylation studies in ME/CFS, LC, and FM, and consider how an integrated cross-condition approach could advance mechanistic insight, enable diagnostic stratification, and improve patient outcomes.