The approach hinges on induced pluripotent stem cells, or iPSCs, which are generated by taking adult cells from a patient and reprogramming them back into an embryonic-like state. From these iPSCs, the researchers coaxed the cells to become myogenic progenitor cells, the precursors that give rise to skeletal muscle. Because these cells carry the complete genetic makeup of the individuals who donated them, they serve as personalized disease models that can be studied in the laboratory without the need for invasive muscle biopsies. The team generated these cells from six people with ME/CFS and seven healthy controls, carefully characterizing them before proceeding to the molecular analysis.

Using RNA sequencing, a technique that captures a snapshot of every gene being actively transcribed in a cell, the researchers compared the transcriptomic profiles between the ME/CFS and control myogenic progenitors. The analysis, conducted with the statistical tool DESeq2, identified seven genes that were differentially expressed at the stringent threshold of adjusted p less than 0.05. These included MIR205HG, FEZF1, HLA-DMB, SLC1A2, SYT13, GALNT4, and SLC2A14. Each of these genes carries its own biological significance. HLA-DMB is involved in immune antigen presentation, SLC1A2 encodes a glutamate transporter critical for neural and muscle signaling, and SYT13 participates in vesicle trafficking. The presence of altered immune-related and signaling-related genes in a muscle progenitor cell type is notable because it bridges two biological domains that have long been suspected in ME/CFS but rarely studied together at this resolution.

Beyond individual genes, the researchers performed gene set enrichment analysis, or GSEA, to identify entire biological pathways that were significantly altered. The results were striking. Seventy-three pathways were significantly enriched, and 96 percent of them were downregulated in the ME/CFS cells. Among the suppressed pathways were those related to cell-cycle regulation, DNA replication, immune responses, and muscle cytoskeletal regulation. The downregulation of cell-cycle and DNA replication pathways suggests that the ME/CFS myogenic progenitors may have a reduced capacity to proliferate and generate new muscle tissue, which could be relevant to the chronic muscle pain and weakness that characterize the illness. The suppression of muscle cytoskeletal regulation pathways points to potential structural and mechanical deficits in how these cells organize their internal scaffolding.

In contrast to the widespread downregulation, one pathway stood out as upregulated in the ME/CFS cells: branched-chain amino acid degradation. Branched-chain amino acids, including leucine, isoleucine and valine, are essential nutrients that muscle tissue metabolizes for energy and protein synthesis. Their accelerated breakdown in the ME/CFS myogenic progenitors could reflect an altered metabolic state in which muscle tissue is being preferentially catabolized, potentially contributing to the fatigue and exercise intolerance that define the condition. This finding aligns with previous reports of mitochondrial alterations and signs of damage in skeletal muscle from people with ME/CFS, although the underlying biological processes had remained poorly understood until now.

To translate these molecular findings into therapeutic possibilities, the researchers turned to the Library of Integrated Network-based Cellular Signatures, or LINCS2, a publicly available database maintained by the United States National Institutes of Health. The LINCS2 database contains gene expression signatures from thousands of drug perturbation experiments, allowing researchers to perform inverse signature matching. The logic is elegant: if a drug reverses the gene expression changes seen in a disease state, that drug might counteract the disease biology. By comparing the ME/CFS gene expression signature against the drug signatures in LINCS2, followed by a supporting literature review, the team identified 21 prioritized drug-repurposing candidates with potential relevance to ME/CFS.

Among the 21 candidates are several approved drugs that may already be familiar. Leflunomide, an immunomodulatory drug used in rheumatoid arthritis, emerged as a candidate because of its potential to counteract the immune-related gene expression changes. Melatonin, a hormone that regulates sleep-wake cycles, was prioritized for its neurological and autonomic relevance. Midodrine, a drug that constricts blood vessels and raises blood pressure in orthostatic hypotension, was identified for its vascular and autonomic properties. The breadth of pharmacological domains represented among the candidates, spanning immune, neurological, autonomic and vascular processes, reflects the multi-system nature of ME/CFS and suggests that no single drug is likely to address all aspects of the illness. Instead, the computational prioritization provides a starting framework for experimental evaluation of drugs that may target different facets of the disease biology.

The significance of this work extends beyond the immediate findings. By establishing patient-derived iPSC myogenic progenitors as a platform for investigating ME/CFS, the researchers have created a tool that can be used for future studies of disease mechanisms, drug screening and biomarker discovery. Because these cells can be generated from any individual with the illness, they enable the study of patient-specific biology without the confounding effects of current medications, acute infections or the logistical challenges of recruiting participants for invasive procedures. The platform also opens the door to longitudinal studies in which cells are generated at different time points from the same patient, potentially capturing the dynamic molecular changes that occur as the illness progresses or responds to interventions.

The study was supported by funding from the National Health and Medical Research Council of Australia, with additional support from the Australian Research Council. Participant recruitment was facilitated by the Geelong ME/CFS Support Group and Emerge Australia, highlighting the critical role that patient advocacy organizations play in enabling this kind of research. The researchers emphasized that the drug-repurposing candidates identified through computational analysis warrant further experimental evaluation before any conclusions can be drawn about their clinical utility. Nevertheless, the convergence of transcriptomic evidence, pathway analysis and drug signature matching provides a rational basis for prioritizing which drugs should be tested first in laboratory models of ME/CFS muscle biology.

As the field of ME/CFS research continues to evolve, studies like this one demonstrate the power of combining stem cell technology with high-throughput molecular analysis and computational drug repurposing. The identification of altered genes and pathways in a muscle-relevant cell type, together with the prioritization of 21 drug candidates, represents a meaningful advance in the effort to understand and ultimately treat a condition that has long resisted conventional approaches. While much work remains to be done to validate these findings and translate them into clinical practice, the study provides a foundation upon which future research can build, offering hope to the millions of people worldwide whose lives have been upended by this devastating illness.

Subject of Research: iPSC-derived myogenic progenitor cells from people with ME/CFS reveal altered genes and pathways with drug repurposing potential

Article Title: iPSC-derived myogenic progenitor cells from people with ME/CFS reveal altered genes and pathways with drug repurposing potential

Article References: Nguyen, D., Truong, T. T. T., Panizzutti, B., Ellis, M., Spolding, B., Swinton, C., Bortolasci, C. C., Bryce, J., Smith, J., Field, C., Liu, Z. S.-J., Kim, J. H., Berk, M., & Walder, K. (2026). iPSC-derived myogenic progenitor cells from people with ME/CFS reveal altered genes and pathways with drug repurposing potential. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09017-w

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09017-w

Keywords: ME/CFS, iPSC, myogenic progenitor cells, RNA sequencing, drug repurposing, skeletal muscle, transcriptomics, Journal of Translational Medicine, iPSC-derived, myogenic, progenitor, cells