Orexinergic and Hypothalamic Dysfunction in Chronic Fatigue Syndrome: A Mechanistic Framework for Biomarker Discovery and Targeted Therapies

Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue, post-exertional malaise, and sleep disturbances, with no definitive diagnostic test. Emerging research suggests a critical role for hypothalamic and orexinergic dysfunction in the pathophysiology of CFS/ME, contributing to impaired sleep-wake regulation, autonomic instability, and metabolic disturbances. This review synthesizes evidence from neuroimaging, endocrine studies, and immunological analyses, highlighting alterations in orexin levels, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and inflammatory cytokine profiles as potential biomarkers. Neuroimaging findings indicate reduced hypothalamic volume and altered functional connectivity, correlating with disease severity. Further, immune-mediated neuroinflammation may disrupt orexinergic signaling, exacerbating fatigue and cognitive dysfunction. The identification of reliable biomarkers—such as cerebrospinal fluid orexin concentrations, neuroimaging markers, and inflammatory profiles—could enhance diagnostic accuracy and refine personalized treatment strategies. Future research should focus on longitudinal studies, pharmacological modulation of orexin receptors, and advanced neuroimaging techniques to elucidate causal mechanisms. Integrating wearable health technologies, cognitive behavioral therapy, and metabolic interventions may improve early detection and disease management. Addressing the public health burden of CFS/ME requires increased research investment, clinical education, and advocacy to improve patient outcomes and reduce diagnostic uncertainty. This review underscores the need for an integrative, precision medicine approach to unravel the complexities of CFS/ME and advance targeted interventions.