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ORIGINAL RESEARCH article

Front. Hum. Neurosci.
Sec. Brain Health and Clinical Neuroscience
Volume 19 - 2025 | doi: 10.3389/fnhum.2025.1509346
This article is part of the Research Topic Shedding Light on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) View all 3 articles

A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study

Provisionally accepted
Li-Yuan Hung Li-Yuan Hung 1Chan Shuo Wu Chan Shuo Wu 1Chia-Jung Chang Chia-Jung Chang 2Peng Li Peng Li 1Kimberly Hicks Kimberly Hicks 3Becky Taurog Becky Taurog 4Joshua J Dibble Joshua J Dibble 1Braxton Morrison Braxton Morrison 1Chimere L Smith Chimere L Smith 4Ronald W Davis Ronald W Davis 2Wenzhong Xiao Wenzhong Xiao 1*
  • 1 Massachusetts General Hospital, Harvard Medical School, Boston, United States
  • 2 School of Medicine, Stanford University, Stanford, California, United States
  • 3 Open Medicine Foundation, Agoura Hills, California, United States
  • 4 Patient Led Research Collaborative, Washington DC, United States

The final, formatted version of the article will be published soon.

    This pilot study harnessed the power of network medicine to unravel the complex pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). By utilizing a network analysis on whole genome sequencing (WGS) data from the Severely Ill Patient Study (SIPS), we identified ME/CFS-associated proteins and delineated the corresponding network-level module, termed the SIPS disease module, together with its relevant pathways. This module demonstrated significant overlap with genes implicated in fatigue, cognitive disorders, and neurodegenerative diseases. Our pathway analysis revealed potential associations between ME/CFS and conditions such as COVID-19, Epstein-Barr virus (EBV) infection, neurodegenerative diseases, and pathways involved in cortisol synthesis and secretion, supporting the hypothesis that ME/CFS is a neuroimmune disorder. Additionally, our findings underscore a potential link between ME/CFS and estrogen signaling pathways, which may elucidate the higher prevalence of ME/CFS in females. These findings provide insights into the pathogenesis of ME/CFS from a network medicine perspective and highlight potential therapeutic targets. Further research is needed to validate these findings and explore their implications for improving diagnosis and treatment.

    Keywords: Network medicine, ME/CFS, chronic fatigue syndrome, neuroimmunology, Neurodegenerative Diseases, Cognitive Disorders, PPI network analysis, Long Covid

    Received: 10 Oct 2024; Accepted: 06 Jan 2025.

    Copyright: © 2025 Hung, Wu, Chang, Li, Hicks, Taurog, Dibble, Morrison, Smith, Davis and Xiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Wenzhong Xiao, Massachusetts General Hospital, Harvard Medical School, Boston, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.