This is day two of a five day series decoding the three most important studies from the past three years for five conditions. Yesterday: PoTS (check it out if you haven’t already!). Today: ME/CFS.
A note before we begin. ME/CFS has spent decades being systematically underfunded, dismissed and excluded from serious scientific inquiry. The three studies below represent a field that has begun to change that, not by proving a single cause, but by finding specific, measurable, biologically coherent abnormalities that accumulate into a picture that is very difficult to dismiss. That progress matters even when individual studies are small, preliminary, or surrounded by caveats.
Study 1: The Protein That Is Physically Dismantling the Mitochondria
Wang PY, Ma J, Kim YC, et al. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the National Academy of Sciences. 2023;120(34):e2302738120.
The story of this study begins with a single patient, a 38-year-old woman with ME/CFS who took days to recover from any physical exertion, whose muscles were consistently failing to produce energy at a normal rate. Researchers at the National Heart, Lung and Blood Institute at the NIH began investigating her cells and found something specific: a protein called WASF3 was present at abnormally high levels in her skeletal muscle, and it was doing something measurable and damaging.
WASF3 is a protein that under normal circumstances has roles in cell migration and structure. When cells are under stress, specifically endoplasmic reticulum (ER) stress, the kind triggered by protein misfolding or metabolic disruption, WASF3 is produced in excess. In this patient, the excess WASF3 was travelling to the mitochondria and physically disrupting the assembly of respiratory supercomplexes.
Respiratory supercomplexes are the protein structures that mitochondria use to produce ATP, the cell’s energy currency. They need to be properly assembled to function. WASF3 was preventing that assembly, leading to reduced oxygen consumption and impaired energy production. The cell’s power plant was being actively sabotaged by one of its own proteins.
The researchers did not stop at a single patient. They obtained skeletal muscle biopsy samples from a broader cohort of ME/CFS patients and found increased WASF3 levels and aberrant ER stress activation across the group, not just in the index case. They then showed that blocking ER stress pharmacologically reduced WASF3 levels and restored mitochondrial function in the patient’s cells.
This is the most specific molecular mechanism identified in ME/CFS to date. It provides a plausible explanation for why ME/CFS patients experience profound exercise intolerance: their mitochondria are being actively disrupted by a stress-induced protein, not simply failing to produce enough energy in a general sense. It also, importantly, identifies a potential therapeutic target. If WASF3 can be reduced by addressing ER stress, and the preliminary cell data suggests it can, that is a tractable drug development direction.
The limitations are real. This was a small study. The cell work was done in vitro and in animal models. The jump from cells and mice to human clinical outcomes is significant. But the finding is specific, mechanistically coherent, and reproducible across multiple ME/CFS patient samples. Published in PNAS, one of the most prestigious multidisciplinary journals in the world, by NIH researchers, it represents the kind of institutional scientific validation ME/CFS has historically been denied.
Study 2: The Most Comprehensive Single Study of ME/CFS Mechanisms Ever Conducted
Walitt B, Nath A, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nature Communications. 2024;15(1):907.
If the WASF3 study found one specific mechanism, this study tried to find all of them simultaneously. Published in Nature Communications in February 2024, it involved 75 investigators across 15 NIH institutes and centres, and at institutions across the US and internationally. Dr Avindra Nath, who led it, called it the most complex study he had ever been part of.
17 people with post-infectious ME/CFS and 21 healthy controls underwent one of the most comprehensive clinical and biological assessments ever applied to ME/CFS patients. Brain imaging. Immune profiling. Autonomic testing. Muscle function. Cardiorespiratory testing. Cognitive assessment. Metabolomics. The study was designed to capture the full biological phenotype rather than test a single hypothesis.
The autonomic findings were striking. ME/CFS participants had higher heart rates throughout the day. Their heart rate failed to drop normally overnight, the nocturnal dip that healthy people experience was blunted or absent. Heart and lung function showed reduced capacity to respond to exercise. These are objective, measurable, physiological differences, not symptom reports.
The immune findings were equally important. ME/CFS participants had higher levels of naive B cells and lower levels of switched memory B cells in the blood compared to healthy controls. This specific immune pattern suggests the immune system is failing to mount appropriate adaptive responses, the kind that help recognise and fight off pathogens the body has encountered before. The researchers proposed that the immune activation triggered by the initial infection is affecting the brain through downstream mechanisms, producing the motor, autonomic and cardiorespiratory dysfunction that characterises the condition.
One finding deserves particular attention: the data showed distinct differences between men and women with ME/CFS. The immune and clinical profiles diverged by sex in ways that suggest ME/CFS is not a single biological entity but a condition with sex-dependent pathophysiology. This has significant implications for both research design and treatment, and it is a finding that most small studies have been unable to detect.
The limitations are significant. 17 participants is a small number, and the study’s rigorous inclusion criteria meant that the most severely affected ME/CFS patients, those unable to attend the NIH Clinical Center for extended assessments, were excluded. The results reflect a specific, relatively early-stage, post-infectious phenotype. They may not represent all ME/CFS presentations. But the depth and rigour of what was done to those 17 people is without parallel in the ME/CFS literature, and the findings provide a foundation for larger, hypothesis-driven studies.
Study 3: The Largest Genetic Study of ME/CFS Ever Conducted
Ponting CP, et al. Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome. medRxiv preprint. August 2025.
I am a geneticist and I conduct GWAS studies as part of my own research. So I want to explain what was done here, why the scale matters, and what the findings actually mean, because genetics has a way of being either oversimplified or made incomprehensible in science communication, and this study deserves neither treatment.
A GWAS scans the entire genome across large numbers of cases and controls, looking for genetic variants that appear more frequently in those with the condition. The power of a GWAS is almost entirely determined by sample size. Rare variants, small effects, and heterogeneous conditions all require large numbers to detect signal above statistical noise. ME/CFS, being heterogeneous and historically underfunded, had never been subjected to a properly powered GWAS until this study.
DecodeME recruited 21,620 ME/CFS cases and 259,909 population controls with European genetic ancestry. This is a sample size that changes what is detectable. It is the difference between trying to spot a signal in static and having a clean frequency range. Funded with £3.2 million from the UK government and co-produced with patients and carers throughout, the study was published as a preprint in August 2025 and is currently undergoing peer review.
Eight genome-wide significant genetic loci were identified. Three of the most significant are located near genes involved in the response to viral and bacterial infection: BTN2A2, OLFM4 and RABGAP1L. This is not coincidental. ME/CFS is characterised by a post-infectious trigger in the majority of cases. Finding that genetic variants near infection-response genes are associated with increased risk of ME/CFS provides the first direct genetic evidence that the immune response to infection is not just a trigger but a biological vulnerability in people who go on to develop the condition.
Four of the eight loci were also associated specifically with cases where post-exertional malaise and fatigue were prominent features, which gives us confidence that the genetic signal is tracking the core features of ME/CFS rather than broader fatigue phenotypes.
The study found a broad global genetic correlation between ME/CFS and traits like insomnia, depression, and neuroticism. However, this requires careful interpretation: when looking at the specific causal risk genes discovered for ME/CFS, there was no direct overlap with depression. This genetic correlation maps vast shared biological networks, not a shared identity, meaning the findings likely point to common neurological and immune mechanisms rather than classifying ME/CFS as a psychological disorder.
The limitations are real and the authors are explicit about them. The sample was predominantly of European ancestry, limiting generalisability. The preprint has not yet completed peer review. As a GWAS of a heterogeneous condition, the eight loci identified likely represent the tip of a much larger genetic architecture. And GWAS identifies associations, not causes: the journey from a genome-wide significant locus to a therapeutic target is long and not guaranteed.
But this is the first time ME/CFS has been mapped genetically at a scale that gives the findings credibility. The signal is in the immune and infection-response biology. The condition is not a psychological phenomenon with a genetic component. It is a biological condition with genetic risk factors pointing toward its immune aetiology.
Honourable Mentions
Three other studies from this period have dedicated pieces on Dysautonomia Decoded. The Appelman biopsy study (Nature Communications, 2024) showed cellular damage, immune infiltration and mitochondrial decline in Long COVID muscle tissue one day after a crash, visible under a microscope (full article breakdown of this has been published, so give that a read!). The Singh brain microstructure study (Frontiers in Medicine, 2026) found microstructural differences in brain tissue in ME/CFS patients using advanced MRI. The Bergquist CSF proteomics study (Scientific Reports, 2026) found distinct protein signatures in spinal fluid linked to autonomic dysfunction and disease severity.
The Bigger Picture
A protein dismantling the mitochondria. A deep phenotyping study finding autonomic, immune and sex-specific abnormalities simultaneously. A genetic map pointing to infection-response biology. These are not the findings of a psychosomatic condition. They are specific, measurable, biologically coherent discoveries that converge on a picture of ME/CFS as a post-infectious, immune-mediated, neurologically expressed condition with a genetic substrate.
The research is moving faster than at any previous point in ME/CFS history. The treatments that this research will eventually generate are not yet here. But the scientific foundation for finding them is being built.
The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.
References
Wang PY, Ma J, Kim YC, et al. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the National Academy of Sciences. 2023;120(34):e2302738120. https://doi.org/10.1073/pnas.2302738120
Walitt B, Nath A, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nature Communications. 2024;15(1):907. https://doi.org/10.1038/s41467-024-45107-3
Ponting CP, et al. Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome. medRxiv preprint. 2025. https://doi.org/10.1101/2025.08.06.25333109
Appelman B, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications. 2024;15:17. https://doi.org/10.1038/s41467-023-44432-3
Singh TB, et al. Microstructural alterations in brain tissue of ME/CFS and Long COVID. Frontiers in Medicine. 2026;13:1824498. https://doi.org/10.3389/fmed.2026.1824498
Bergquist J, Xiao W, et al. Proteomic signatures in cerebrospinal fluid in ME/CFS. Scientific Reports. 2026. https://doi.org/10.1038/s41598-026-46965-1
Thank you for such a clear and accessible summary for us non-subject matter experts! 🩵
Fascinating 🧐