Study Identifies Shared Biological Pathways Behind Chronic Fatigue in Five

A study published in the journal *Translational Medicine* has identified a shared biological mechanism that may explain chronic fatigue experienced by patients with five distinct diseases. Researchers from the University of East Anglia and Oxford Biodynamics collaborated with the London School of Hygiene & Tropical Medicine and the Cornwall Partnership NHS Foundation Trust to conduct the work.

Five Conditions Linked by Common Pathways

The five conditions examined were long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-traumatic stress disorder (PTSD), rheumatoid arthritis, and multiple sclerosis. Although their causes differ, patients across all five often report overlapping symptoms — most notably severe fatigue, cognitive fog, impaired concentration, sleep disturbances, and reduced capacity to perform daily activities. The research team sought to determine whether this symptom convergence reflects shared underlying biology.

3D Genome Mapping Reveals Network-Level Connections

To investigate, the team used Oxford Biodynamics’ EpiSwitch Orion platform, which enables analysis of the three-dimensional architecture of the genome — moving beyond standard DNA sequence analysis. They integrated genomic data from prior studies involving all five conditions and examined how genes interact within cellular networks. While direct gene-to-gene overlap among disease-associated genes was limited, clear commonalities emerged when those genes were mapped onto broader biological networks.

Core Systems Affected Across All Five Diseases

These shared network connections centered on five key biological systems: immune regulation and inflammation; mitochondrial energy production; metabolism; stress response; and neuroendocrine signaling. Professor Dmitri Beshizitsky, the study’s lead researcher, stated that the findings suggest diseases with different origins may ultimately converge on the same biological systems — potentially accounting for their overlapping clinical presentations.

Key Genes Identified, Including LAG3

The researchers pinpointed several hub genes within these networks, including *LAG3*, a gene associated with T-cell exhaustion following prolonged activation. However, they emphasized that the functional roles of these genes require further validation through additional studies.

Why Fatigue Persists After Initial Triggers Fade

The team proposed that dysregulation in these shared pathways could explain why fatigue endures in some patients even after the initiating factor has resolved. In long COVID, for example, certain immune responses may persist beyond acute infection; in PTSD, psychological trauma may alter stress hormone pathways and inflammatory responses. Though these triggers differ, their downstream effects may intersect in energy production and immune regulation circuits.

Potential for Objective Blood-Based Diagnostics

The findings open the possibility of developing blood tests to support more objective diagnosis of these conditions. Current diagnosis of ME/CFS, long COVID, and related syndromes relies heavily on symptom reporting, as no globally accepted laboratory test exists for any of them. A prior study using the EpiSwitch platform showed promising results for a blood test targeting ME/CFS, though further validation is needed before clinical use.

Next Steps: Biomarkers and Targeted Therapies

Beshizitsky noted that the researchers hope the new findings will aid development of biomarkers for diagnostic use and, in the longer term, inform therapies directed at the shared biological pathways. The team stressed that the results do not indicate the five diseases are a single condition, but rather suggest they may share biological mechanisms contributing to overlapping symptoms — particularly chronic fatigue.