10 points summary of the proposed "2025 disease mechanism" for ME/CFS

Based on research and emerging models as of late 2025, this is a 10 points summary of the proposed disease mechanism for ME/CFS: 

Genetic Susceptibility: ME/CFS patients exhibit a polygenic vulnerability with specific DNA variations impacting the immune system, endoplasmic reticulum (ER), mitochondria, calcium signaling, Locus Coeruleus (LC)-hypothalamus connectivity, synaptic function, and neuronal maintenance. (1, 2)

Impaired Pathogen Clearance: This genetic susceptibility compromises the elimination of protein fragments post-viral infection (e.g., via TAP1 variants), leading to persistent antigen presentation and chronic immune signaling. (3, 4) 

Chronic Endoplasmic Reticulum Stress: Persistent immune activation and the resulting cellular stress induce a state of chronic endoplasmic reticulum (ER) stress within high-metabolism tissues like neurons and muscle cells. (5, 6)

Mitochondrial Dysfunction via WASF3: Chronic ER stress triggers the upregulation of the WASF3 protein, which directly interferes with mitochondrial respiratory supercomplex assembly and function, thereby reducing ATP production. (5, 6)

Post-Exertional Malaisie (PEM): This systemic ER stress and compromised mitochondrial energy production manifest in skeletal muscles and the brain as profound fatigue and the hallmark symptom of Post-Exertional Malaise (PEM). (7, 8)

Locus Coeruleus (LC) Dysfunction: Locus Coeruleus neurons suffer from "impaired drive," characterized by an energy deficit and a "pre-synaptic vesicle energy problem" that prevents efficient norepinephrine signaling and recovery. (9)

Reduced CRH Neurons in the Hypothalamus:  A breakthrough autopsy study found that ME/CFS patients had significantly lower levels of Corticotropin Releasing Hormone (CRH) -producing neurons in the hypothalamus, providing the first physical evidence of a permanent "crash" in the HPA axis. (10).

Faulty Neural Wiring: Dysregulated calcium signaling (e.g., via ANO3, RYR2 variants) plays a critical role in the "faulty wiring" and hyperexcitability observed in core brain regulatory circuits. (11)

Cumulative Gene Effects: Individual combinations of these DNA variations determine the severity, symptom profile, and progression of the disease phenotype. A study identified over 22,000 "reproducible disease signatures", which are combinations of 1 to 4 SNPs that were more common in ME/CFS patients than in healty controls. (2)

The Vicious Cycle & Comorbidities: The positive feedback loop of overexertion leading to metabolic and neurological breakdown drives disease progression and severe hypersensitivity, ultimately leading to comorbidities like Multiple Chemical Sensitivity (MCS) and Electromagnetic Hypersensitivity (EHS). (11)

I hope that research in 2026 will confirm and deepen these findings.

(I used artificial intelligence (AI) via https://www.google.com/ to create this list. Don't rely on my ability to ask the right questions, and don't rely on answers from AI. But, please, be inspired to search for more information.)

More information

Persistent viral antigens as significant drivers of the Endoplasmic Reticulum stress that induces high levels of WASF3

Potential triggers for ME/CFS, persistent antigen presentation and a unified pathomechanism for ME/CFS

Hit, Stay and Sabotage: A failure to clear viral fragments in ME/CFS

"Faulty Wiring" in the brain in ME/CFS patients - a structural and genetic failure

Dysreguleret samspil mellem Locus Coeruleus, hypothalamus, SCGN og HSD11B1 hos ME/CFS patienter (in Danish - please, use google translate)

Can low norepinephrine content in vesicles explain reduced oxygen extraction in ME/CFS?

References

1) Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

2) Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID
JM Sardell, S Das, M Pearson, D Kolobkov, AR Malinowski, LM Fullwood, M Sanna, H Baxter, K McLellan, M Natt, D Lamirel, S Chowdhury, MA Strivens, S Gardner
medRxiv 2025.12.01.25341362; doi: https://doi.org/10.64898/2025.12.01.25341362
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
https://www.medrxiv.org/content/10.64898/2025.12.01.25341362v1

3) Walitt B, Singh K, LaMunion SR, Hallett M, Jacobson S, Chen K, Enose-Akahata Y, Apps R, Barb JJ, Bedard P, Brychta RJ, Buckley AW, Burbelo PD, Calco B, Cathay B, Chen L, Chigurupati S, Chen J, Cheung F, Chin LMK, Coleman BW, Courville AB, Deming MS, Drinkard B, Feng LR, Ferrucci L, Gabel SA, Gavin A, Goldstein DS, Hassanzadeh S, Horan SC, Horovitz SG, Johnson KR, Govan AJ, Knutson KM, Kreskow JD, Levin M, Lyons JJ, Madian N, Malik N, Mammen AL, McCulloch JA, McGurrin PM, Milner JD, Moaddel R, Mueller GA, Mukherjee A, Muñoz-Braceras S, Norato G, Pak K, Pinal-Fernandez I, Popa T, Reoma LB, Sack MN, Safavi F, Saligan LN, Sellers BA, Sinclair S, Smith B, Snow J, Solin S, Stussman BJ, Trinchieri G, Turner SA, Vetter CS, Vial F, Vizioli C, Williams A, Yang SB; Center for Human Immunology, Autoimmunity, and Inflammation (CHI) Consortium; Nath A. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun. 2024 Feb 21;15(1):907. doi: 10.1038/s41467-024-45107-3. PMID: 38383456; PMCID: PMC10881493.

https://www.nature.com/articles/s41467-024-45107-3

4) Palomo IM, Cox B, Williams MV, Ariza ME. Chronic Reactivation of Persistent Human Herpesviruses EBV, HHV-6 and VZV and Heightened Anti-dUTPase IgG Antibodies Are a Recurrent Hallmark in Post-Infectious ME/CFS and is Associated With Fatigue. J Med Virol. 2026 Jan;98(1):e70769. doi: 10.1002/jmv.70769. PMID: 41451845.

https://pubmed.ncbi.nlm.nih.gov/41451845/

5) Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159; PMCID: PMC10450651.
https://pubmed.ncbi.nlm.nih.gov/37579159/

6) Syed AM, Karius AK, Ma J, Wang PY, Hwang PM. Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Physiology (Bethesda). 2025 Jul 1;40(4):0. doi: 10.1152/physiol.00056.2024. Epub 2025 Feb 17. PMID: 39960432; PMCID: PMC12151296.
https://pubmed.ncbi.nlm.nih.gov/39960432/

7) Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR, Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion, Molecular & Cellular Proteomics (2025), doi: https://doi.org/10.1016/j.mcpro.2025.101467.
https://www.sciencedirect.com/science/article/pii/S1535947625005663

8) Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights
August Hoel, Fredrik Hoel, Sissel Elisabeth Furesund Dyrstad, Henrique Chapola, Ingrid Gurvin Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Karl Albert Brokstad, Hans-Peter Marti, Olav Mella, Øystein Fluge, Karl Johan Tronstad
medRxiv 2025.05.28.25328245; doi: https://doi.org/10.1101/2025.05.28.25328245
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
https://www.medrxiv.org/content/10.1101/2025.05.28.25328245v1

9) Health Rising

Role Reversal: Could a WEAKENED Fight/Flight Response Be Causing ME/CFS and Long COVID? The 2025 IACFS/ME Conference Pt. I

10) Health Rising

ME/CFS Autopsy Study Finds a Wrecked HPA Axis: The 2025 IACFS/ME Conference Report #3

11) Follow ME in Denmark

 "Faulty Wiring" in the brain in ME/CFS patients - a structural and genetic failure