NEW RESEARCH has shown that Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is linked to simultaneous disruptions in energy metabolism, immune regulation, and vascular function. Australian researchers report that these concurrent changes may explain the complexity of symptoms and open pathways to earlier diagnosis.
Unravelling The Biological Basis Of ME/CFS
Myalgic encephalomyelitis, also known as chronic fatigue syndrome, remains one of the most poorly understood long term conditions in medicine. Patients experience persistent fatigue, post exertional malaise, cognitive difficulties, and a range of systemic symptoms, yet clinicians lack reliable diagnostic tests. Previous research into ME/CFS has tended to focus on single biological systems in isolation, producing fragmented insights. The new study, led by Macquarie University, addresses this gap by examining multiple biological domains at the same time, offering a more integrated picture of ME/CFS pathophysiology.
Multimodal Analysis Reveals ME/CFS Signatures
The researchers compared whole blood samples from 61 people meeting clinical criteria for ME/CFS with samples from 61 healthy age and sex matched controls. White blood cells from participants with ME/CFS showed clear signs of cellular energy stress, including higher levels of adenosine monophosphate and adenosine diphosphate, alongside reduced ATP generation. Immune profiling demonstrated a shift towards less mature T lymphocyte, dendritic cell, and natural killer cell subsets. Plasma protein analysis identified elevated markers linked to endothelial activation and blood vessel remodelling, while immunoglobulin-related proteins were reduced. Using classification and regression tree modelling, a machine learning approach, the team identified a combination of seven biological variables strongly associated with ME/CFS. This predictive model highlights interactions between energy, immune, and vascular dysfunction rather than a single dominant abnormality.
Implications For Clinical Practice and Future Research
For clinicians, these findings reinforce that ME/CFS is a multisystem disorder requiring a holistic diagnostic approach. If validated in larger cohorts, combined biomarker models could reduce diagnostic delays and support earlier intervention. The study also suggests that therapeutic strategies may need to target energy metabolism, immune maturation, and vascular health simultaneously. Future research will need to assess how these biological signatures evolve over time and whether they can guide personalised treatment. Ultimately, a clearer biological framework for ME/CFS could improve patient outcomes and reduce the long-standing burden associated with delayed recognition and limited management options.
Reference
Heng B et al. Mapping the complexity of ME/CFS: evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction. Cell Reports Medicine. 2025;DOI:10.1016/j.xcrm.2025.102514.
