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Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
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Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 August 2025 | Viewed by 32037

Special Issue Editor

Prof. Dr. Elisa Oltra

E-Mail Website
Guest Editor
Biomedicine, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain
Interests: development of quantitative differential diagnostic test for ME/CFS, fibromyalgia and post-COVID-19 condition; disclose the underlying pathomechanisms leading to metabolic and immune dysfunctions in ME/CFS, fibromyalgia and post-COVID-19 condition with a focus on genetic-epigenetic interactions

Special Issue Information

Dear Colleagues,

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), classified by the WHO with the international classification of diseases (ICD-11) 8E49 code as “post-viral fatigue syndrome”, in the section for “diseases of the nervous system”, is a chronic multisystem highly disabling disease characterized by post-exertional malaise, often causing brain fog, intestinal and sleep disturbances, and pain. Impactfully, according to the U.S. CDC center for statistics data, published in December 2023, the disease affects 1.3% of the adult population, with 0.7% of the age of 18 to 39, and with a preference for women (2:1). The numbers appear to have increased when compared to previous epidemiology data (0.86% of the adult population). Due to the lack of established biomarkers for the clinic, ME/CFS diagnosis still relies on clinical case definitions, and treatments are directed to palliate symptoms. Understanding disease triggers and the reasons leading to chronic disease, at the molecular level, seems necessary to improve ME/CFS healthcare and to advance the development of preventive programs.

This Special Issue invites the submission of original research articles, reviews, opinion articles, and case reports, presenting the current advancements in the molecular processes that are associated with ME/CFS, the response to treatments, and any additional information that helps elevate the current understanding of the disease.

Prof. Dr. Elisa Oltra
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
  • diagnosis
  • post-exertional malaise (PEM)
  • comorbidity
  • biomarker
  • therapy
  • immunity
  • microbiome

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Published Papers (4 papers)

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Research

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18 pages, 1560 KiB  
Article
Heat vs. Fatigue: Hyperthermia as a Possible Treatment Option for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
by Barbara Hochecker, Katja Matt, Melanie Scherer, Alica Meßmer, Alexander von Ardenne and Jörg Bergemann
Int. J. Mol. Sci. 2025, 26(11), 5339; https://doi.org/10.3390/ijms26115339 - 1 Jun 2025
Viewed by 2468
Abstract
The aetiology and pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have not yet been clarified. Its exact diagnosis is also difficult because it has no biomarkers. This lack of knowledge leads to difficulties in treating the disease. In our work, we are attempting [...] Read more.
The aetiology and pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have not yet been clarified. Its exact diagnosis is also difficult because it has no biomarkers. This lack of knowledge leads to difficulties in treating the disease. In our work, we are attempting to counteract this problem by analysing the central cellular mechanisms in ME/CFS patients and comparing them with those of healthy individuals. This pilot study provides a small glimpse into the journey of nine people with ME/CFS—more specifically, how their peripheral blood mononuclear cells (PBMCs) responded immediately after a session of whole-body hyperthermia (WBH). The clinical effect of WBH has already been investigated in other studies on the treatment of ME/CFS, and these studies have provided valuable insights into its potential benefits. The present study is concerned with the investigation of cellular parameters, namely autophagy, mitochondrial function and mRNA expression, before and after WBH. The results suggest that ME/CFS patients may have higher autophagy-related protein light chain 3 (LC3)-II levels and increased mitochondrial function compared with healthy individuals. A whole-body hyperthermia session could lead to a reduction in LC3-II levels, resulting in a reversion to the levels observed in healthy donors. In the case of mitochondrial parameters, hyperthermia could lead to an increase in the measured parameters. This pilot study is a continuation of a previously published study in which only the isolated cells of ME/CFS patients and a healthy control group were treated with hyperthermia. Full article
(This article belongs to the Special Issue Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)
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40 pages, 8055 KiB  
Article
Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by James N. Baraniuk
Int. J. Mol. Sci. 2025, 26(3), 1282; https://doi.org/10.3390/ijms26031282 - 1 Feb 2025
Cited by 2 | Viewed by 22262
Abstract
Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and [...] Read more.
Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS. Full article
(This article belongs to the Special Issue Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)
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Review

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22 pages, 749 KiB  
Review
Cognitive Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Aetiology and Potential Treatments
by Amolak Singh Bansal, Katharine A. Seton, Jonathan C. W. Brooks and Simon R. Carding
Int. J. Mol. Sci. 2025, 26(5), 1896; https://doi.org/10.3390/ijms26051896 - 22 Feb 2025
Viewed by 5402
Abstract
Systemic infection and inflammation impair mental function through a combination of altered attention and cognition. Here, we comprehensively review the relevant literature and report personal clinical observations to discuss the relationship between infection, peripheral inflammation, and cerebral and cognitive dysfunction in patients with [...] Read more.
Systemic infection and inflammation impair mental function through a combination of altered attention and cognition. Here, we comprehensively review the relevant literature and report personal clinical observations to discuss the relationship between infection, peripheral inflammation, and cerebral and cognitive dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Cognitive dysfunction in ME/CFS could result from low-grade persistent inflammation associated with raised pro-inflammatory cytokines. This may be caused by both infectious and non-infectious stimuli and lead to altered regional cerebral blood flow accompanied by disturbed neuronal function. Immune dysregulation that manifests as a subtle immunodeficiency or the autoimmunity targeting of one or more neuronal receptors may also be a contributing factor. Efforts to reduce low-grade systemic inflammation and viral reactivation and to improve mitochondrial energy generation in ME/CFS have the potential to improve cognitive dysfunction in this highly disabling condition. Full article
(This article belongs to the Special Issue Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)
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Other

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15 pages, 643 KiB  
Case Report
HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab
by Eva Martín-Martínez, Sara Gil-Perotin, Karen Giménez-Orenga, Lucas Barea-Moya and Elisa Oltra
Int. J. Mol. Sci. 2025, 26(10), 4885; https://doi.org/10.3390/ijms26104885 - 20 May 2025
Viewed by 1123
Abstract
This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow-up, which provided a secondary diagnosis of Multiple Sclerosis (MS) eight years later. The most impactful result was his response to rituximab treatment after the [...] Read more.
This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow-up, which provided a secondary diagnosis of Multiple Sclerosis (MS) eight years later. The most impactful result was his response to rituximab treatment after the systematic failure of prior treatments. Although the expression of endogenous retroviral proteins has been associated with autoimmunity, the patient did not show increased expression of the toxic protein HERV (human endogenous retrovirus)-W ENV, a target of the ongoing clinical trials with temelimab in MS and long COVID-19 cases. However, genome-wide HERV transcriptome analysis by high density microarrays clearly revealed a distinct profile in the patient’s blood supportive of an altered immune system. Limitations of the study include sub-optimal frequency of magnetic resonance imaging to monitor lesion progression, and similarly for reassessment of HERV profiles after rituximab. Overall, the coincidence of HERV alterations and the impactful response to rituximab presents the possibility of additional, more specific, therapeutic targets encoded by other HERV elements yet to be discovered. Full article
(This article belongs to the Special Issue Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)
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