Unraveling the Biological Mechanisms of Chronic Fatigue: A Multifaceted Approach

Chronic fatigue, particularly in the context of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-viral syndromes, represents a growing public health challenge. While post-exertional malaise is considered a hallmark symptom, research suggests a broader interplay of mitochondrial dysfunction, neuroinflammation, immune dysregulation, and metabolic abnormalities. Despite the urgent need for improved diagnostics and treatments, consensus on disease mechanisms remains fragmented.

This Research Topic welcomes interdisciplinary contributions that push the boundaries of our current understanding. Particularly we seek to investigate molecular biomarkers that distinguish chronic fatigue from overlapping syndromes, and explore neuroimmune and metabolic pathways to uncover disease mechanisms. Other areas of interest include innovative diagnostic tools using neuroimaging, omics technologies, and artificial intelligence, and novel therapeutic interventions tailored to the pathophysiological drivers of fatigue.

By contributing to this Research Topic, you will help shape the future of chronic fatigue research and accelerate the development of precision medicine strategies that can meaningfully improve patient care. Key areas of interest include:

Pathophysiology and Mechanisms:
   o   Investigating the biological drivers of chronic fatigue, including mitochondrial dysfunction, neuroinflammation, oxidative stress, immune dysregulation, and metabolic imbalances.
   o   Exploring multi-omics approaches (genomics, transcriptomics, proteomics, and metabolomics) to reveal novel molecular pathways.
   o   Using advanced neuroimaging and systems biology models to map fatigue-related brain alterations.

Diagnostic Approaches:
   o   Identifying biomarkers and immune signatures to improve diagnostic precision.
   o   Integrating AI-driven algorithms and machine learning models for early detection.
   o   Addressing comorbidities and confounding factors that complicate differential diagnosis.

Clinical Manifestations and Comorbidities:
   o   Examining how chronic fatigue overlaps with fibromyalgia, autoimmune diseases, chronic pain syndromes, and psychiatric disorders.
   o   Investigating the gut-brain axis and microbiome disturbances in fatigue syndromes.
   o   Understanding the role of autonomic nervous system dysfunction in fatigue severity.

Therapeutic Interventions:
   o   Evaluating novel pharmacological treatments, including immunomodulators, metabolic enhancers, and mitochondrial-targeted therapies.
   o   Assessing the role of precision nutrition, circadian rhythm interventions, and wearable technology in fatigue management.
   o   Exploring multi-modal rehabilitation approaches, including biomarkers in cognitive-behavioral therapy, neuromodulation, and physical therapy.

Patient Experiences and Quality of Life:
   o   Investigating the psychosocial impact of chronic fatigue, including barriers to healthcare access and disability-related challenges.
   o   Developing patient-centered outcome measures to guide personalized treatment.
   o   Incorporating patient-reported experiences to inform public health policies and clinical guidelines.


Topic Editor Prof. Leonard Calabrese is a consultant for AbbVie, Amgen, Sanofi, AstraZeneca, Jansen, BMS, and Fate Therapeutics, has been a speaker for Sanofi, AstraZeneca, and GSK, and is part of the advisory board for OpenEvidence. All other Topic Editors declare no conflicts of interest.

Keywords: chronic fatigue, post-viral fatigue, myalgic encephalomyelitis, ME/CFS, mitochondrial dysfunction, neuroinflammation, biomarkers, precision medicine, systems biology, machine learning, immune-metabolic dysfunction

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.