Charting the circulating proteome in ME/CFS using cross-system profiling to uncover mechanistic insights

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition often triggered by infections, with unclear mechanisms and no established biomarkers or treatments. We apply aptamer-based serum proteomics to 50 ME/CFS patients and 29 healthy controls, analyzing 7,326 protein targets. We identify 1,823 aptamers with significant differences between the groups (845 after false discovery rate [FDR] correction). Distinct patterns of tissue- and process-specific changes are seen. There is a broad increase in secreted proteins, while intracellular proteins, e.g., from skeletal muscle, particularly show reduction. Immune cell-associated signatures indicate immune reprogramming, including a distinct reduction in proteins secreted by activated neutrophils. Focused secretome analysis supports intensified regulatory interactions related to immune activity, inflammation, vasculature, and metabolism. Validation of measurements using antibody-based methods confirms findings for a selection of proteins. The uncovered serum proteome patterns in ME/CFS patients may contribute to understanding the pathophysiology and inform future biomarker research and therapeutic development.