Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition often triggered by infections. The underlying mechanism remains poorly understood, and diagnostic markers and effective treatments are presently lacking. We performed aptamer-based serum proteomics in 54 ME/CFS patients and 27 healthy controls and identified 1823 of 7326 aptamers reporting differences between the groups (845 after false discovery rate (FDR) correction). Distinct patterns of tissue- and process-specific changes were seen. There was a broad increase in secreted proteins, while intracellular proteins, e.g. from skeletal muscle, particularly showed reduction. Immune cell-specific signatures indicated immune reprogramming, including a distinct reduction in neutrophil-associated proteins. Focused secretome analysis supported intensified regulatory interactions related to immune activity, inflammation, vasculature, and metabolism. Validation of measurements using antibody-based methods confirmed findings for a selection of proteins. The uncovered serum proteome patterns in ME/CFS patients help clarify a multifaceted pathophysiology and offer a foundation for future therapy and biomarker discovery efforts.