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

Abstract Background The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remains unknown, and no validated disease models, biomarkers, or effective treatments are currently available. Debilitating fatigue and post-exertional malaise, together with chronic muscle pain and weakness, are hallmarks of ME/CFS. Indeed, skeletal muscle from people with ME/CFS has been reported to exhibit signs of damage and mitochondrial alterations, although the underlying biological processes remain poorly understood. This study used patient-derived induced pluripotent stem cell (iPSC)-derived myogenic progenitor (MP) cells to investigate ME/CFS-associated transcriptomic differences and identify potential drug-repurposing candidates. Methods MP cells were generated from iPSCs derived from people with ME/CFS and healthy controls and characterised. RNA sequencing was performed to compare transcriptomic profiles between ME/CFS and control MPs ( n = 6 and n = 7, respectively). Differentially expressed genes and pathways were identified using DESeq2 and gene set enrichment analysis (GSEA), followed by drug-repurposing analysis using the Library of Integrated Network-based Cellular Signatures (LINCS2) database 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 significantly enriched pathways, 96% of which were downregulated in ME/CFS MPs, including pathways related to cell-cycle regulation, DNA replication, immune responses, and muscle cytoskeletal regulation. In contrast, branched-chain amino acid degradation was upregulated. LINCS2-based inverse signature matching followed by literature review identified 21 prioritised drug-repurposing candidates with potential relevance to ME/CFS. These included approved drugs such as leflunomide, melatonin, and midodrine, spanning pharmacological domains related to immune, neurological, autonomic, and vascular processes and warranting further experimental evaluation. Conclusions Patient-derived iPSC-MPs provide a useful platform for investigating ME/CFS-associated transcriptional differences in a muscle-relevant cell type. The findings support further investigation of skeletal muscle-related molecular processes in ME/CFS and provide a basis for experimental evaluation of computationally prioritised drug-repurposing candidates.