Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome

2025/08/11 by Anne Gardella, Daniel Eweis-LaBolle, Conor Loy +7 · 1 voice · 5 citations
Immunology and Microbiology · Medicine · #Biology #Chronic fatigue syndrome #Encephalomyelitis #Fibromyalgia and Chronic Fatigue Syndrome Research #Gene #Genetics #IL-33, ST2, and ILC Pathways #Immune Cell Function and Interaction #Immune system #Immunology #Internal medicine #Medicine #Multiple sclerosis #RNA

paper · pdf · doi:10.1073/pnas.2507345122

published in Proceedings of the National Academy of Sciences 122(33), e2507345122 (National Academy of Sciences)

openalex publication_date 2025/08/11 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

People living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience heterogeneous and debilitating symptoms that lack sufficient biological explanation, compounded by the absence of accurate, noninvasive diagnostic tools. To address these challenges, we explored circulating cell-free RNA (cfRNA) as a blood-borne bioanalyte to monitor ME/CFS. cfRNA is released into the bloodstream during cellular turnover and reflects dynamic changes in gene expression, cellular signaling, and tissue-specific processes. We profiled cfRNA in plasma by RNA sequencing for 93 ME/CFS cases and 75 healthy sedentary controls, then applied machine learning to develop diagnostic models and advance our understanding of ME/CFS pathobiology. A generalized linear model with least absolute shrinkage selector operator regression trained on condition-specific signatures achieved a test-set AUC of 0.81 and an accuracy of 77%. Immune cfRNA deconvolution revealed differences in platelet-derived cfRNA between cases and controls, as well as elevated levels of plasmacytoid dendritic, monocyte, and T cell-derived cfRNA in ME/CFS. Biological network analysis further implicated immune dysfunction in ME/CFS, with signatures of cytokine signaling and T cell exhaustion. These findings demonstrate the utility of RNA liquid biopsy as a minimally invasive tool for unraveling the complex biology behind chronic illnesses.

Citations

• The multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue
• Tropism of human pegivirus (formerly known as GB virus C/hepatitis G virus) and host immunomodulation: insights into a highly successful viral infection

Cited by

• Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum
• Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome. [europepmc]
• Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum. [europepmc]
• Toward a Molecular Reclassification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Integrating Multi-Omics, Machine Learning, and Precision Medicine. [europepmc]

Discussions

• 🔮 Was das bedeutet: Erstmals könnte es einen objektiven, blutbasierten Test für ME/CFS geben. Das würde Diagnosezeiten verkürzen, Stigma reduzieren und gezieltere Therapien ermöglichen. 🔗 www.doi.o [bsky, 15 points, 0 comments]

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