Orexinergic and Hypothalamic Dysfunction: An Integrative Review with a Focus on Precision Medicine in Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a complex multisystem disorder marked by unrelieved fatigue, post-exertional malaise, and unrefreshing sleep. The lack of validated biomarkers and the heterogeneity in pathophysiology challenge diagnosis and treatment. Recent evidence implicates hypothalamic and orexinergic dysfunction in the regulation of stress, sleep, metabolism, and immune responses. To synthesize and critically appraise empirical and theoretical evidence linking orexinergic and hypothalamic alterations to the pathophysiology of CFS, with a focus on biomarker discovery and precision-therapeutic implications. This integrative review followed the Whittemore and Knafl framework. Comprehensive searches (PubMed, Scopus, Web of Science, OpenAlex) spanning 2000–2025. Data from neuroimaging, endocrine, and immunological domains were thematically and quantitatively synthesized. Methodological rigor was ensured through an adapted Joanna Briggs appraisal. Structural MRI and DTI revealed hypothalamic atrophy and reduced frontoparietal white-matter integrity correlating with fatigue and cognitive impairment. Hormonal profiling confirmed hypocortisolism and thyroid axis alterations. Cerebrospinal fluid orexin-A levels were decreased in subsets of patients. Cytokine dysregulation (IL-6, TNF-α) was associated with neuroinflammation, sleep disruption, and autonomic dysfunction. These findings converge on a feedback model where HPA-axis and orexin deficits sustain systemic dysregulation and chronic symptomatology. This review proposes a unifying framework positioning orexinergic-hypothalamic dysfunction as a central mechanism in CFS/ME. A multimodal biomarker panel and therapeutic strategies targeting the orexin–HPA–inflammation axis are warranted. Future directions include interventional trials with orexin receptor modulators and machine-learning approaches to stratify patient endotypes for personalized care.