iPSC-Derived Myogenic Progenitor Cells from People with ME/CFS Reveal Altered Genes and Pathways with Drug Repurposing Potential

Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterised by profound fatigue, post-exertional malaise, muscle pain and weakness. Although skeletal muscle abnormalities and mitochondrial alterations have been reported in people with ME/CFS, the underlying biological processes remain poorly understood, and no validated disease models, biomarkers or effective treatments are currently available. This study used patient-derived induced pluripotent stem cell (iPSC) myogenic progenitor (MP) cells to investigate intrinsic transcriptomic abnormalities in ME/CFS and identify potential drug repurposing candidates. Methods MP cells were generated from iPSCs derived from people with ME/CFS and healthy controls, and successfully characterised. Global mRNA sequencing was performed to compare transcriptomic profiles between ME/CFS and control MP cells (n = 6 ME/CFS; n = 7 controls). Differentially expressed genes and pathways were identified, followed by drug repurposing analysis using the Library of Integrated Network-based Cellular Signatures drug database (LINCS2) and supporting literature review. Results RNA sequencing identified seven differentially expressed genes at adjusted p < 0.05, including MIR205HG , FEZF1 , HLA-DMB , SLC1A2 , SYT13 , GALNT4 , and SLC2A14 . Pathway analysis identified 73 differentially expressed pathways, of which 96% were downregulated in ME/CFS MP cells. Downregulated pathways included those involved in cell cycle regulation, DNA replication, mismatch repair, immune response and muscle cytoskeleton regulation-related pathways. In contrast, upregulated pathways were associated with metabolic reprogramming, including increased reliance on branched-chain amino acids for energy production. These findings suggest intrinsic abnormalities in ME/CFS-derived MP cells, particularly involving metabolic regulation, mitochondrial function and muscle-related cellular processes. Based on the differentially expressed genes, LINCS2-based drug repurposing analysis and literature review identified 22 candidate drugs with potential relevance to ME/CFS. These included safe and widely available agents such as leflunomide, melatonin and midodrine, which target pathways related to antiviral defence, immunomodulation, neurotransmitter modulation, autonomic regulation and vascular function. Conclusions Patient-derived iPSC-MP cells provide a useful model for investigating intrinsic skeletal muscle-related abnormalities in ME/CFS. Transcriptomic profiling revealed altered pathways related to cell cycle regulation, immune function, cytoskeletal organisation and energy metabolism, supporting the involvement of mitochondrial and metabolic dysfunction in ME/CFS pathobiology. Drug repurposing analysis identified several clinically relevant candidates that may warrant further functional validation as potential therapeutic options for ME/CFS.