Category: Biomarker

Authors’ Response to “Comment on ‘SMPDL3B as a novel biomarker and therapeutic target in myalgic encephalomyelitis’”

Letter:

We thank Chen and Yan for their thoughtful and positive comments on our recent publication and for their interest in the translational implications of SMPDL3B biology in myalgic encephalomyelitis (ME) [, ]. Their letter provides a welcome opportunity to clarify methodological points related to biomarker validation, in vitro pharmacological assays, and mechanistic interpretation []. We appreciate this constructive dialogue and address each issue below in a collegial and scientifically grounded manner.

Read the rest of this letter HERE>>

Source: Rostami-Afshari B, Elremaly W, Franco A, Moreau A. Authors’ Response to “Comment on ‘SMPDL3B as a novel biomarker and therapeutic target in myalgic encephalomyelitis'”. J Transl Med. 2026 Jan 16;24(1):75. doi: 10.1186/s12967-025-07583-z. PMID: 41546078; PMCID: PMC12809929. https://pmc.ncbi.nlm.nih.gov/articles/PMC12809929/ (Full text)

People with ME/CFS have a consistent faulty cellular structure, new research confirms

Press Release:

A faulty ion channel function is a consistent biological feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), providing long-awaited validation for hundreds of thousands of Australians living with the debilitating illness.

The new Griffith University research found a crucial cellular structure responsible for calcium transport, the TRPM3 ion channel, was faulty in immune cells from people with ME/CFS.

The paper “Large-scale investigation confirms TRPM3 ion channel dysfunction in ME/CFS” has been published in Frontiers in Medicine.

Director and senior author, Professor Sonya Marshall-Gradisnik from Griffith’s National Center for Neuroimmunology and Emerging Diseases (NCNED), said the TRPM3 played an essential role in calcium transport into cells, regulating responses properly in the body, immune function, and maintaining normal cellular balance.

“When it fails, cells cannot function properly as calcium signaling is essential for healthy immune cell activity,” Professor Marshall-Gradisnik said.

“Our findings provide clear and definitive scientific evidence that TRPM3 ion channels are not working properly in people with ME/CFS.”

Read the rest of this press release HERE>>

Large-scale investigation confirms TRPM3 ion channel dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease hallmarked by multiple systemic symptoms, such as neurocognitive, respiratory, immunological, gastrointestinal, and cardiovascular impairment, which worsen following physical and mental exertion. ME/CFS is characterized by an elusive pathomechanism, profound impact on quality of life, and an absence of diagnostic tests or evidence-based treatments. Transient Receptor Potential Melastatin 3 (TRPM3) ion channel has been suggested as a potential biomarker and target for therapeutics in people with ME/CFS, supported by a series of publications reporting genetic and protein changes. This study aimed to undertake a multi-site, large-scale investigation to determine the consistency of TRPM3 ion channel dysfunction in people with ME/CFS.

Methods: TRPM3 ion channel activity was assessed in two distinct laboratory sites by independent investigators using whole-cell patch-clamp recordings performed in isolated natural killer (NK) cells from 36 ME/CFS participants, characterized according to the Canadian Consensus Criteria, and 42 healthy controls. The Mann–Whitney U test was used to compare endogenous TRPM3-like currents between cohorts. The effect of location was determined using a covariance analysis, while antagonist sensitivity was determined using Fisher’s Exact test.

Results: Electrophysiological experiments revealed a significant reduction in TRPM3 function in NK cells from individuals diagnosed with ME/CFS compared with controls in all parameters analyzed. Importantly, there was no significant effect of the laboratory sites on the results of this investigation, which confirms TRPM3 as a consistent biomarker for ME/CFS.

Conclusion: The current large-sample-size study confirmed previous results regarding TRPM3 ion channel dysfunction in NK cells in ME/CFS, demonstrating involvement of TRPM3 in the pathomechanism of this condition. Therefore, this multiple-site investigation offers strong evidence demonstrating TRPM3 as a potential biomarker for the diagnosis of ME/CFS, given the accumulating evidence.

Source: Sasso Etianne Martini , Er Teagan S. , Eaton-Fitch Natalie , Hool Livia , Muraki Katsuhiko , Marshall-Gradisnik Sonya. Large-scale investigation confirms TRPM3 ion channel dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Frontiers in Medicine, Volume 12 – 2026. https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1703924 10.3389/fmed.2025.1703924 ISSN=2296-858X https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1703924/full (Full text)

Wheat and chaff in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory

To the Editor,

We read the contribution by Hunter et al., titled “Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling” in this journal, initially impressed for the large collection of data. They actually presented a novel, genome-wide epigenetic profiling approach using EpiSwitch® technology to identify potential diagnostic biomarkers for ME/CFS [1]. The use of 3D chromatin conformation signatures provides a fresh perspective on disease-specific gene regulation, moving beyond conventional transcriptomics and methylation analyses. In general, the diagnostic model demonstrates impressive sensitivity (92%) and specificity (98%) in distinguishing ME/CFS patients from controls, suggesting real clinical potential [1]. Moreover, the application of advanced machine learning techniques adds analytical robustness, while pathway analysis identifies biologically plausible immune-related mechanisms. This integrative approach sets a promising foundation for future biomarker-driven diagnostics and personalized therapy stratification in ME/CFS. Fundamentally, they presented a retrospective case-control analysis aiming to identify diagnostic epigenetic markers for ME/CFS using 3D chromatin conformation profiling (EpiSwitch®). However, while the authors make bold claims regarding diagnostic sensitivity and specificity, the paper suffers from multiple scientific weaknesses and methodological ambiguities that undermine its validity and translational relevance.

First, the article repeatedly asserts that “immune dysregulation” is a hallmark of ME/CFS, citing elevated pro-inflammatory cytokines and natural killer (NK) cell dysfunction. However, whereas the authors cite updated papers with a presumptive relationship with the issue, a critical omission here is the lack of citation of early foundational immunological studies in ME/CFS [2]. Notably absent is the 1994 work by Tirelli et al. in the Scandinavian Journal of Immunology, which documented, for the first time, immunological abnormalities in CFS patients and could serve as an important historical anchor for claims of immune dysregulation [2]. This omission raises concerns about reporting bias and selective citation to frame the narrative around newer, possibly more aligned findings with the current study methodology [2, 3].

Additionally, the paper refers to “ME/CFS inclusion criteria” as requiring severe CFS with patients being “housebound,” but fails to specify which diagnostic criteria were used, whether the Fukuda, Canadian Consensus, International Consensus, or IOM/NAM criteria [1]. This lack of precision is critical, as different case definitions yield different cohorts in terms of clinical features and biological signatures. Using “severe housebound” as a criterion, without reference to a validated clinical definition or stratification tool (e.g., Bell Disability Scale), introduces subjectivity and undermines the reproducibility of patient selection. The term “housebound” is not a recognized diagnostic stratifier and suggests imprecise cohort construction.

Further ambiguity arises when the authors discuss the control group. They state that controls had “none of the four key CFS symptoms present or in the past” and “preferably an existing history of glandular fever or COVID.” The phrase “preferably” is ambiguous and methodologically problematic [1]. Did the control group actually include individuals with prior infectious mononucleosis or COVID-19, and if so, how were these illnesses verified? The phrase “preferably” suggests either inconsistency in selection or retrospective rationalization, both of which compromise the clarity and control of variables in the study. Furthermore, it is scientifically incoherent to describe individuals as controls (i.e., free from ME/CFS) while also including those with a known post-infectious risk profile, potentially biasing the control group with latent post-viral immunogenetic changes [1].

There is further conceptual confusion when the authors state that the ME/CFS network reveals some overlap with pathways involved in multiple sclerosis (MS) and rheumatoid arthritis (RA). While such overlaps are plausible and worth exploring, the authors do not sufficiently explain the biological rationale for this claim or its relevance to ME/CFS pathophysiology [1]. They reference IL-2, IL-10, CD4, and TLR pathways as shared elements, but these are highly pleiotropic and non-specific immunological signals.

The mere presence of these markers in ME/CFS does not imply mechanistic similarity to MS or RA. Without longitudinal or functional studies, this comparison becomes speculative and possibly misleading, especially given the known heterogeneity of ME/CFS and the distinct immunopathology of autoimmune diseases like MS.

Read the rest of this letter HERE.

Source: Tirelli U, Franzini M, Chirumbolo S. Wheat and chaff in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory. J Transl Med. 2026 Jan 5;24(1):20. doi: 10.1186/s12967-025-07397-z. PMID: 41491817. https://link.springer.com/article/10.1186/s12967-025-07397-z (Full text)

Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK Biobank

Highlights:

  • ME/CFS shows distinct genetic influences on metabolic regulation.
  • Lipid and hormone-related pathways emerge as key areas of interest.
  • Many small genetic effects may collectively disrupt metabolic resilience in ME/CFS.

Summary:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a clinically heterogeneous disease lacking approved therapies. To assess genetic susceptibility towards a specific metabolic phenotype, we performed a genome-wide association study on plasma biomarker levels (mGWAS) in ME/CFS patients (n=875) and healthy controls (HCs) (n=36,033).
We identified 112 significant SNP–biomarker associations in ME/CFS, compared with 4,114 in HCs. Two SNPs specific to ME/CFS, mapping to HSD11B1 and SCGN, were associated to phospholipids in extra-large very low-density lipoproteins (VLDL) and total fatty acids respectively. Genetic effects of VLDL associations were among the least correlated between ME/CFS and HCs. Heterogeneity tests found differential effects for several lipid traits at ADAP1, NR1H3 and CD40, which are involved in immune regulation.
ME/CFS mGWAS summary statistics were decomposed to uncover shared genetic-metabolic patterns, where enrichment analysis highlighted pathways in lipid metabolism, neurotransmitter transport, and inflammation. These findings provide a genetic and molecular rationale for patient heterogeneity and suggest a polygenic predisposition in which many small-effect variants may jointly perturb metabolic mechanisms.
Source: Katherine Huang, Muhammad Muneeb, Natalie Thomas, Elena K. Schneider-Futschik, Paul R. Gooley, David B. Ascher, Christopher W. Armstrong. Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK Biobank. iScience, 2025, 114316 ISSN 2589-0042, https://doi.org/10.1016/j.isci.2025.114316. https://www.sciencedirect.com/science/article/pii/S2589004225025775 (Full text available as PDF file)

Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in Myalgic Encephalomyelitis

Abstract:

Myalgic Encephalomyelitis (ME) is a complex, multisystem disorder with poorly understood pathophysiological mechanisms. SMPDL3B, a membrane-associated protein expressed in renal podocytes, is essential for lipid raft integrity and glomerular barrier function. We hypothesize that reduced membrane-bound SMPDL3B may contribute to podocyte dysfunction and impaired renal physiology in ME. To investigate this, we quantified soluble SMPDL3B in plasma and urine as a surrogate marker of membrane-bound SMPDL3B status and assessed renal clearance and plasma metabolomic profiles.
In a cross-sectional study of 56 ME patients and 16 matched healthy controls, ME patients exhibited significantly lower urine-to-plasma ratios of soluble SMPDL3B and reduced renal clearance, suggesting podocyte-related abnormalities. Plasma metabolomics revealed dysregulation of metabolites associated with renal impairment, including succinic acid, benzoic acid, phenyllactic acid, 1,5-anhydroglucitol, histidine, and citrate.
In ME patients, plasma SMPDL3B levels inversely correlated with 1,5-anhydroglucitol concentrations and renal clearance. Multivariable modeling identified the urine-to-plasma SMPDL3B ratio as an independent predictor of clearance. Female ME patients showed more pronounced SMPDL3B alterations, reduced clearance, and greater symptom severity. Non-linear associations between soluble SMPDL3B and lipid species further suggest systemic metabolic remodeling.
These findings support soluble SMPDL3B as a potential non-invasive biomarker of renal-podocyte involvement in ME, highlighting sex-specific differences that may inform future therapeutic strategies.
Source: Rostami-Afshari B, Elremaly W, McGregor NR, Huang KJK, Armstrong CW, Franco A, Godbout C, Elbakry M, Abdelli R, Moreau A. Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in Myalgic Encephalomyelitis. International Journal of Molecular Sciences. 2025; 26(18):8882. https://doi.org/10.3390/ijms26188882 https://www.mdpi.com/1422-0067/26/18/8882 (Full text)

The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers

Abstract:

Chronic fatigue syndrome (CFS) is a complex disease involving multiple systems throughout the body with unknown pathogenesis and is characterized by chronic fatigue. To date, no effective treatment for CFS has been found, as well as biomarkers for early identification of diagnosis. However, exosomes, a subpopulation of extracellular vesicles (EVs), are membranous vesicles secreted by cells into the surrounding environment, and long noncoding RNAs (LncRNAs) in EVs can mediate inter-organ and inter-cellular communication, which maybe associate with CFS.

Therefore, this study aims to review the association between EV-LncRNAs and CFS, and to explore whether LncRNAs can be used as potential biomarkers for early identification and diagnosis of CFS, which put forward new ideas and a theoretical basis for the pathogenesis of CFS, as well as the identification of novel targeted therapies.

Source: Wang Lei , Xu Yujia , Zhong Xiang , Wang Guiping , Shi Zijun , Mei Can , Chen Linwanyue , Zhan Jianbo , Cheng Jing. The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers. Frontiers in Molecular Biosciences. Volume 12 – 2025 https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1653627/full (Full text)

Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a chronic, multisystem illness characterized by post-exertional malaise (PEM) and cognitive dysfunction, yet the molecular mechanisms driving these hallmark symptoms remain unclear. This study investigated haptoglobin (Hp) as a potential biomarker of PEM severity and cognitive impairment in ME, with a focus on Hp phenotypes and structural proteoforms.

Methods: A longitudinal case-control study was conducted in 140 ME patients and 44 matched sedentary healthy controls. In the discovery phase, global plasma proteomic profiling was performed in 61 ME patients and 20 controls before and after a standardized, non-invasive stress protocol in order to induce PEM. Associations between Hp levels, phenotype, and cognitive performance were assessed. In the validation phase, plasma Hp concentrations and proteoform composition were analyzed in an independent cohort of 89 ME patients and 24 controls using high-performance liquid chromatography (HPLC).

Results: ME patients demonstrated a significant reduction in Hp levels following post-exertional stress. Lower baseline Hp concentrations were associated with impaired cognitive performance. Hp phenotypes were differentially associated with symptom burden, with the Hp2-1 phenotype enriched in ME and linked to greater PEM severity and cognitive deficits compared to Hp1-1 and Hp2-2. HPLC analysis revealed altered Hp proteoform profiles in the Hp2-1 subgroup, including increased high-mass tetrameric and pentameric forms and shorter retention times indicative of structural changes. In contrast, the Hp1-1 phenotype was associated with milder symptoms and greater cognitive resilience.

Conclusions: These findings suggest that Hp phenotype and proteoform structure modulate the physiological response to post-exertion in ME, offering insight into the molecular basis of PEM and its clinical heterogeneity. Hp may serve as a translational biomarker for patient stratification and a potential therapeutic target to mitigate oxidative stress and cognitive dysfunction in ME.

Source: Moezzi A, Ushenkina A, Widgren A, Bergquist J, Li P, Xiao W, Rostami-Afshari B, Leveau C, Elremaly W, Caraus I, Franco A, Godbout C, Nepotchatykh O, Moreau A. Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis. J Transl Med. 2025 Aug 28;23(1):970. doi: 10.1186/s12967-025-07006-z. PMID: 40877900. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-07006-z (Full text)

Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia

Abstract:

Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations.

In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0-50 pg/mL), normal (51-200 pg/mL), and high (>200 pg/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM.

Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM.

These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.

Source: Azimi G, Elremaly W, Elbakry M, Franco A, Godbout C, Moreau A. Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia. Int J Mol Sci. 2025 Aug 8;26(16):7670. doi: 10.3390/ijms26167670. PMID: 40868993. https://www.mdpi.com/1422-0067/26/16/7670 (Full text)