Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management

Abstract

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has garnered substantial scientific and clinical interest, due to its rising global prevalence and significant pathophysiological overlap with post-acute COVID-19 syndrome (PACS). This review systematically elucidates the prevailing diagnostic criteria, summarizes recent advances in understanding the potential pathophysiological mechanisms, and evaluates pharmacological and non-pharmacological interventions, and symptom-based assessment and management strategies.

Methods

A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and the Cochrane Library for articles published from inception to August 2025.

Results

Current diagnostic frameworks for ME/CFS rely primarily on clinical symptomatology and lack definitive biomarkers. Immune dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation are central to its pathology. Pharmacological management includes immunomodulatory treatments, antioxidant therapies, mitochondrial support, and neuroinflammation intervention. Non-pharmacological strategies such as cognitive behavioral therapy (CBT), graded exercise therapy (GET), activity pacing, and traditional Chinese medicine (TCM) complement biomedical approaches by alleviating symptom severity and promoting energy conservation.

Conclusion

Among these approaches, CBT serves as an adjunctive therapy for symptom management rather than a curative one, whereas GET is contraindicated due to its potential for harm. Comprehensive clinical assessment and management of ME/CFS requires being symptom oriented and the recognition of individual differences. Recommended directions for future research include developing biomarker-based diagnostic tools, optimizing combination therapies that target multiple pathophysiological pathways simultaneously, and integrating real-world data and digital health technologies for precise monitoring and management of ME/CFS.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-025-07506-y.

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by persistent, unexplained fatigue that is not alleviated by rest and is frequently exacerbated by minimal physical or mental exertion [1]. Profound fatigue persisting for over 6 months is a hallmark symptom of ME/CFS [2]. Patients with ME/CFS often experience various symptoms beyond fatigue, such as post-exertional malaise (PEM), orthostatic intolerance, sleep disturbances, muscle pain, headaches, and cognitive difficulties [3]. Notably, the associated cognitive dysfunction can impair academic and occupational performance, thus increasing psychological distress [4]. It is reported that the female-to-male prevalence of ME/CFS in England is 3.88:1, with a peak prevalence of about 6:1 among individuals in the fourth and fifth decades of life [5]. Studies have reported a clinical overlap between post-acute COVID-19 syndrome (PACS) and ME/CFS, such as fatigue, PEM, nonrestorative sleep, and brain fog [6]. An estimated 10–20% of COVID-19 patients experience lingering symptoms beyond 6 months after mild to moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [7–9]. The symptoms overlap between PACS and post-infection fatigue syndrome suggest a potential common viral etiology, particularly involving pathogens associated with the onset of ME/CFS [10]. It has been reported that nearly half of the patients experiencing PACS meet the 2003 Canadian Consensus Criteria for ME/CFS at 6 months after SARS-CoV-2 infection [11]. The estimated prevalence of ME/CFS varies widely with the adopted diagnostic criteria, ranging from 1.41% (Oxford criteria) and 0.89% (Fukuda criteria) to 0.79% (Australian criteria) and 0.17% (Holmes criteria) [12]. In the United States, ME/CFS carries an annual economic burden of approximately $18 billion to $51 billion [13]. The substantial clinical, societal, and economic burden of ME/CFS make it a serious public health concern, warranting urgent attention from researchers, clinicians, and policymakers [13, 14].

The inconsistency in diagnostic standards and case definitions for ME/CFS poses a major obstacle to its clinical diagnosis. It is estimated that up to 91% of ME/CFS patients in the United States and approximately 60% in Europe remain undiagnosed. Furthermore, even diagnosed patients are frequently subjected to inappropriate treatments [2, 15]. Owing to the insufficient understanding of its pathophysiology, the management of ME/CFS remains contentious and lacks evidence-based treatment protocols. Therefore, this review aims to: (1) elucidate the prevailing diagnostic criteria for ME/CFS; (2) summarize recent advances in understanding the potential pathophysiological mechanisms of ME/CFS; (3) evaluate pharmacological and non-pharmacological interventions; and (4) review symptom-based assessment and management strategies.

Methods

The narrative review was reported and conducted in accordance with the SANRA (the Scale for the Assessment of Narrative Review Articles) [16]. A comprehensive literature search was performed across four electronic databases: PubMed, Web of Science, Embase, and the Cochrane Library from their inception to August 2025. The primary search terms were: “myalgic encephalomyelitis”, “chronic fatigue syndrome”, “ME/CFS”, “diagnosis”, “pathophysiology”, and “treatment.” A comprehensive search strategy was developed using both Medical Subject Headings (MeSH) and free-text terms. The eligibility criteria were as follows: (1) Studies were published in English; (2) Studies focused on the diagnosis, pathophysiology, assessment or treatment of ME/CFS, including pharmacological, non-pharmacological, and traditional Chinese medicine (TCM) interventions. The exclusion criteria included: (1) Publications without accessible full text; (2) Duplications. Two reviewers (JF and JJ) independently screened the eligibility based on abstracts and titles. Disagreements were resolved by discussion or consultation with a third reviewer (XW). Ultimately, a total of 211 publications were included in this narrative review.

Diagnostic strategies for ME/CFS

Since the Centers for Disease Control and Prevention (CDC) formally named ME/CFS and established its first diagnostic criteria in 1988, the diagnostic criteria have evolved through various editions of clinical case definitions [17]. The Fukuda criteria were established in 1991 and provided a comprehensive definition of chronic fatigue syndrome (CFS). This framework required the presence of severe, persistent fatigue for at least six months that was not attributable to exertion or other medical conditions [18]. The 1994 CDC criteria for ME/CFS further clarified that the fatigue must be persistent, not substantially alleviated by rest, and not the result of ongoing exertion [19]. The 2003 Canadian criteria significantly expanded the clinical case definition for ME/CFS by incorporating accompanying neurological and immunological manifestations into the diagnostic process. This revision represented a paradigm shift, acknowledging the condition’s multifactorial etiology, which encompassed factors such as viral infections and immune system dysfunction [20]. Subsequent frameworks, the 2007 National Institute for Health and Care Excellence (NICE) criteria [21] and 2015 Institute of Medicine (IOM) criteria [22] further refined and updated the diagnostic approach. Across all diagnostic frameworks, fatigue constitutes the mandatory core symptom, with a required duration of at least 3 to 6 months. Table 1 offers a comparative overview of these diagnostic frameworks.

Table 1.

The different diagnostic criteria for ME/CFS

	1988 CDC criteria(17)	1991 Oxford criteria(18)	1994 CDC criteria(19)	2003 Canadian criteria(20)	2007 NICE criteria(21)	2015 IOM criteria(22)
Core Symptom Focus	Chronic fatigue	Fatigue	Chronic fatigue	Fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain.	Fatigue with all of the following features: new or had a specific onset, persistent and/or recurrent, unexplained fatigue, has resulted in a substantial reduction in activity level, characterised by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 h, with slow recovery over several days).	The core symptoms focus on fatigue, postexertional malaise and unrefreshing sleep.
Other symptoms	Other symptoms include sore throat, lymph node pain, headache, myalgia, arthralgia, mild fever, sleep disturbance, neuropsychologic complaints, among others.	Myalgia, mood, sleep disturbance	Four or more of the following symptoms: impairment in short-term memory or concentration, sore throat, tender lymph nodes, muscle and joint pain, headaches, unrefreshing sleep, postexertional malaise.	Two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations.	One or more of the following symptoms: headaches, sleep disturbances, cognitive dysfunction, muscle and/or joint pain, painful lymph nodes without pathological enlargement, sore throat, physical or mental exertion makes symptoms worse, general malaise or ‘flu-like’ symptoms, dizziness and/or nausea, palpitations in the absence of identified cardiac pathology.	Cognitive impairment or orthostatic intolerance.
Mental health factor	Neuropsychologic complaints (one or more of the following complaints: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, depression).	Other psychiatric disorders (including depressive illness, anxiety disorders, and hyperventilation syndrome) are not necessarily reasons for exclusion.	Presence of mental health issues, such as anxiety disorders and less severe forms of depression, does not exclude.	Mental health issues are not synonymous with CFS, but can coexist.	Not primarily a mental health condition.	Not explicitly mentioned as a core criterion.
Duration of Fatigue	The duration of fatigue must be at least 6 months	Fatigue present for at least 6 months, more than 50% of the time.	Fatigue lasting 6 or more consecutive months.	The illness persists for at least 6 months. Three months is appropriate for children.	4 months in an adult and 3 months in a child or young person.	Fatigue must persist for more than 6 months.
Exclusion Criteria	Exclusion criteria require thorough evaluation to rule out other conditions that could cause similar symptoms, such as malignancy, autoimmune diseases, localized infection, among others.	Medical conditions known to produce chronic fatigue. Current diagnosis of schizophrenia, manic depressive illness, substance abuse, eating disorder or organic brain disease.	Any active medical condition that may explain the presence of chronic fatigue; Unresolved prior illnesses; Major psychiatric disorders; Substance abuse, and severe obesity.	Exclude active disease processes that explain most of the major symptoms of fatigue, sleep disturbance, pain, and cognitive dysfunction.	The diagnosis of CFS/ME should be reconsidered if none of the following key features are present: postexertional fatigue or malaise, cognitive difficulties, sleep disturbance and chronic pain.	Not explicitly detailed, but the diagnosis of systemic exertion intolerance disease (ME/CFS) should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
Subtypes	No specific subtypes are mentioned.	Chronic fatigue syndrome and Post-infectious fatigue syndrome.	Chronic Fatigue Syndrome and Idiopathic Chronic Fatigue.	None specified.	None specified.	None specified.
Physical examination/laboratory examination	The recommended evaluation includes weight measurements; temperature measurements; complete blood count and differential; serum electrolytes; glucose; creatinine, blood urea nitrogen, among others.	Physical examination by a competent physician.	Includes thorough history, mental status examination, physical examination, and minimum battery of laboratory tests.	Includes musculoskeletal, neurological, cardiorespiratory, endocrine, immune, gastrointestinal system evaluations and routine laboratory tests.	A physical examination and assessment of psychological wellbeing should be carried out, such as urinalysis for protein, blood and glucose, full blood count, urea and electrolytes, liver function, thyroid function, among others.	Tests are used to support the diagnosis when needed.
Application purpose	Provide a working definition for the CFS designed to enhance the comparability and reproducibility of clinical research and epidemiological studies, and to provide a rational basis for evaluating patients who have chronic fatigue of undetermined cause.	To provide a basis for fruitful research studies and interdisciplinary collaboration.	To foster a systematic and comprehensive approach to data collection about CFS and similar illnesses.	The objective was to provide a flexible conceptual framework for clinical diagnoses.	Increasing the recognition of ME/CFS, influencing practice in the ‘real world’, improving access to appropriate services, and supporting consistent service provision, emphasising the need for multidisciplinary working, among others.	To “recommend whether new terminology for ME/CFS should be adopted”; and to create plans for disseminating these conclusions to clinicians.

CDC: Disease Control and Prevention. NICE: National Institute for Health and Care Excellence. IOM: Institute of Medicine. CFS: Chronic fatigue syndrome. ME/CFS: Myalgic encephalomyelitis/chronic fatigue syndrome

Currently, the diagnostic criteria for ME/CFS predominantly rely on patient-reported symptoms, such as fatigue, PEM, cognitive impairment, and orthostatic intolerance. The subjective nature of relying on patient-reported symptoms poses a significant risk of misdiagnosis or underdiagnosis. Emerging research on ME/CFS has uncovered potential biomarkers, metabolic disturbances, and neuroimaging abnormalities, paving the way for new strategies in early diagnosis and tracking disease progression [23, 24]. In a recent study [25], nuclear magnetic resonance analysis of blood plasma metabolomic profiles from ME/CFS patients with comorbidities revealed significant lipoprotein anomalies. Based on these findings, a diagnostic model with robust discriminatory performance (AUC=0.83) was developed. Azcue et al. [26] identified elevated plasma neurofilament light chain (NfL) levels in ME/CFS patients, which was correlated with cognitive deficit and autonomic dysfunction, thus implicating NfL as a promising biomarker for neuroaxonal damage and associated neurological dysfunction in ME/CFS. A novel nanoelectronic assay was developed for diagnosis of ME/CFS by detecting a distinct impedance pattern in the peripheral blood mononuclear cells (PBMCs) of patients under hyperosmotic stress. A supervised machine learning classifier was trained on impedance signal, highlighting its potential as a diagnostic biomarker for ME/CFS [27]. Furthermore, Germain et al. [28] identified disrupted acyl lipid and steroid metabolism in ME/CFS patients, in contrast to healthy controls. Provenzano et al. [29] developed a logistic regression model using machine learning on functional magnetic resonance imaging (fMRI) data, which differentiated ME/CFS patients from healthy controls with high accuracy (80% or 76%) and revealed a distinct ME/CFS-associated pattern of brain activation. Given the accumulating evidence from biomarkers, metabolic disturbances, and neuroimaging, future research should focus on integrating multimodal approaches to establish robust diagnostic tools for ME/CFS.

Pathophysiological mechanisms of ME/CFS

Immune dysregulation in ME/CFS

Accumulating evidence underscores the significant role of immune dysregulation in the pathogenesis of ME/CFS [30, 31]. Immune anomalies promote chronic inflammation and contribute to the exacerbation of clinical symptoms in ME/CFS [32]. Elucidating the nature of immune dysfunction in ME/CFS paves the way for developing targeted therapies to improve patient outcomes.

Inflammatory cytokine dysregulation and chronic inflammation in ME/CFS

Current evidence suggests that chronic low-grade inflammation, mediated by an imbalance between pro- and anti-inflammatory cytokines, is a pivotal mechanism in ME/CFS. Notably, elevated levels of pro-inflammatory cytokines, such as interleukin-1beta(IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), have been consistently observed in patients with ME/CFS [33, 34]. IL-1β is known to directly induce fatigue and malaise through stimulating the hypothalamic-pituitary-adrenal axis and inflammatory signaling pathways in the central nervous system (CNS) [35, 36]. TNF-α promotes chronic inflammation that drives muscle pain and fatigue [37–40]. In contrast, elevated IL-6 correlates with increased severity of fatigue and cognitive impairment [41, 42]. As an initiator of the inflammatory cascade, IL-1β induces IL-6 production, thereby amplifying inflammation through T-helper 1 (Th1) and T-helper 17 (Th17) immune responses. In turn, Th1 cells produce IFN-γ and Th17 cells generate interleukin-17, which collectively contribute to sustained immune dysregulation and chronic inflammation [43–46]. TNF-α stimulates the production of IL-1β and IL-6, thereby reinforcing a positive feedback loop that sustains inflammation [47]. Simultaneously, IFN-γ disrupts the blood-brain barrier (BBB), thus facilitating the entry of peripheral inflammatory mediators into the CNS and contributing to neuroinflammation and neurological symptoms [48, 49].

The dysregulation of anti-inflammatory cytokines, such as interleukin-13 [50] and transforming growth factor-beta1 [51], compromises the critical balance with pro-inflammatory signals, thereby preventing the resolution of inflammation and leading to its chronic persistence. Taken together, the aforementioned evidence underscores the critical importance of immune dysregulation in ME/CFS pathogenesis, thereby positioning it as a key area for future research.

Dysregulated immune cell function in ME/CFS

ME/CFS patients demonstrate significant immune dysregulation, particularly in T cell and B cell functions [30, 52, 53]. Recent findings highlight a dysregulation characterized by a T-helper 1 (Th1)/T-helper 2 (Th2) imbalance, which promotes abnormal immune responses, ultimately contributing to the disease pathology [54]. Th1 cells, which mediate cellular immune responses against intracellular pathogens, exhibit reduced functionality in ME/CFS. Similarly, Th2 cells, which are responsible for promoting humoral immunity and antibody production, are disrupted in ME/CFS [55]. The Th1/Th2 imbalance in ME/CFS drives broader immune dysregulation, including overreaction to pathogens and mismanagement of immune responses against host tissues, potentially contributing to the autoimmune features of ME/CFS. Elevated Th2 responses in ME/CFS patients may reflect immune priming, increasing susceptibility to adverse reactions after physical exertion [56]. The increase in Th2-associated cytokines can perpetuate systemic inflammation and exacerbate hallmark symptoms such as fatigue and musculoskeletal pain [57]. Bradley et al. [58] discovered that a subset of patients with ME/CFS displayed B cell hyperactivity, indicating its potential contribution to disease pathogenesis via autoimmune-mediated mechanisms. These findings suggest that the immune system misidentifies self-antigens, which in turn drives the production of pathogenic autoantibodies [30].

In addition, the dysfunction of Natural Killer (NK) cells in ME/CFS compromises their ability to combat viral infections. This may render patients particularly susceptible to viral reactivation, as seen with pathogens such as Epstein-Barr virus (EBV) and cytomegalovirus [59, 60]. Impaired NK cell function drives sustained immune activation and chronic inflammation, thereby providing a mechanistic link between viral reactivation and the exacerbation of symptoms [61]. The relationship between viral infections and immune dysfunction thereby supports the hypothesis that ME/CFS arises from an initial infection which leads to persistent immune dysregulation.

Redox imbalance in ME/CFS

ME/CFS is frequently associated with a state of elevated oxidative stress and diminished antioxidant capacity, which in turn contributes to mitochondrial impairment, nervous system injury, and chronic inflammation.

Elevated production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in ME/CFS

Several studies have demonstrated increased oxidative stress and mitochondrial dysfunction in ME/CFS [62, 63]. Shankar et al. [64] documented elevated oxidative stress and impairments in ROS clearance pathways in patients with ME/CFS and PACS, notably within memory lymphocytes. Gottschalk et al. [65] identified elevated levels of autophagy-related protein 13 in the serum of ME/CFS patients, which is known to promote the production of ROS and nitric oxide (NO) in microglial cells. Mitochondria produce ROS during adenosine triphosphate (ATP) generation, with some electrons leaking from the electron transport chain (ETC), which subsequently leads to superoxide anion production [66]. An overproduction of ROS can overwhelm the cellular antioxidant defenses, thereby causing oxidative stress [67]. Additionally, pro-inflammatory cytokines such as TNF-α, IL-1β, and IFN-γ boost ROS production via mitochondrial and nicotinamide adenine dinucleotide phosphate oxidase pathways [68, 69]. This process upregulates inducible NO synthase (iNOS), leading to excessive NO. The subsequent reaction between NO and superoxide generates peroxynitrite [70].

Compromised antioxidant defense systems in ME/CFS

ME/CFS is associated with a dysregulated antioxidant defense system, featuring depletion of antioxidant molecules and reduced enzymatic activity, which directly results in an impaired capacity to eliminate excess ROS. It is reported that compromised redox status and diminished antioxidant levels are correlated with the severity of symptoms in ME/CFS patients [71].

1. Glutathione (GSH) depletion in ME/CFS

   GSH plays a critical role in protecting cells from oxidative damage by neutralizing free radicals. However, ME/CFS patients exhibit significantly diminished GSH levels, thereby rendering them more susceptible to oxidative stress and the associated cellular damage. Hampilos et al. [72] identified an association between a specific GSH peroxidase 1 gene variant and reduced cerebral GSH levels in ME/CFS patients, which may exacerbate oxidative stress. Furthermore, a marked reduction in GSH activity was detected in individuals with idiopathic chronic fatigue [73]. Collectively, GSH depletion exacerbates mitochondrial dysfunction, immune dysregulation, and hallmark clinical symptoms, including fatigue and cognitive impairment, in ME/CFS.

2. Reduced antioxidant enzyme activity in ME/CFS

   Research has revealed that the activity of key antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and GSH peroxidase (GPx) is attenuated in ME/CFS patients, which consequently aggravates oxidative stress. SOD is a critical first-line defense against oxidative damage, converting superoxide radicals into hydrogen peroxide. Subsequently, CAT and GPx facilitate the breakdown of H₂O₂ into nontoxic water and oxygen [64]. A comparative analysis of ME/CFS and PACS revealed a shared signature of oxidative stress, characterized by diminished SOD activity, and GPx4-mediated lipid peroxidation. These disruptions in redox homeostasis suggest impaired clearance of superoxide radicals, which in turn perpetuates a cycle of oxidative stress [64]. An investigation demonstrated a distinct oxidative stress profile in idiopathic chronic fatigue, characterized by significantly diminished levels of SOD and CAT and concurrently elevated oxidative stress biomarkers compared to healthy controls [73].

Mitochondrial dysfunction in ME/CFS

Mitochondrial dysfunction is implicated as a key pathogenic process in ME/CFS, underpinned by mechanisms involving oxidative and nitrosative stress, immune-inflammatory pathways, and metabolic disturbances.

Impaired energy metabolism

In ME/CFS, mitochondrial dysfunction is associated with reduced ATP production, thereby contributing to core symptoms such as persistent fatigue and PEM. Research has revealed a significantly reduced rate of ATP synthesis by Complex V in the PBMCs of ME/CFS patients [62]. Complex V catalyzes the final step of oxidative phosphorylation by converting adenosine diphosphate to ATP. Attenuated Complex V efficiency leads to insufficient ATP production. Furthermore, the efficiency of ATP production in mitochondria depends on maintaining the proton gradient across the inner mitochondrial membrane. It has been observed that ME/CFS patients exhibit an increased proton leak, which diverts energy from ATP synthesis [62]. Energy production is further worsened by exertion, to the extent that even minimal activity can severely deplete the constrained energy reserves.

Metabolic dysregulation

Multiple metabolic abnormalities have been implicated in the pathophysiology of ME/CFS. A comparative study of fatty acid oxidation in isolated circulating NK, CD4+, and CD8 + T cells revealed elevated lipid metabolism in ME/CFS patients compared with healthy controls, particularly under conditions of high energy demand [74]. Mandarano et al. [75] examined T cell metabolism in 53 ME/CFS patients in comparison with 45 healthy controls by isolating CD4⁺ and CD8⁺ T cells. Their results showed that the both T cell types exhibited decreased glycolysis rates, with the CD8⁺ T cells also displaying impaired glycolysis following activation. Furthermore, a metabolic profiling study of 200 ME/CFS patients identified diminished serum amino acids essential for oxidative metabolism, alongside elevated expression of pyruvate dehydrogenase kinases (PDKs) in PBMCs, which inhibited pyruvate dehydrogenase (PDH). ME/CFS patient serum induces metabolic changes in myoblasts, including excessive lactate, which indicates that PDH dysfunction underlies PEM and inadequate ATP generation [76]. Given its central role in linking glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle, a deficiency in PDH activity can disrupt efficient ATP production. The above evidence converges to support the hypothesis that metabolic dysregulation, characterized by impaired glycolysis and PDH dysfunction, underlies the mitochondrial dysfunction observed in ME/CFS.

Neuroinflammation in ME/CFS

BBB dysfunction

The BBB is composed of endothelial cells connected by tight junctions and maintains brain homeostasis by regulating the exchange of substances between the blood and the CNS. In ME/CFS, the integrity of the BBB may be compromised, thereby allowing peripheral inflammatory mediators to infiltrate the brain and induce neuroinflammation. BBB dysfunction in ME/CFS can be triggered by various stressors, including viral infections, chemical exposure, and chronic stress. Symptom onset in ME/CFS is frequently associated with prior viral infections, such as EBV, human herpesvirus-6, and herpes simplex virus (HSV-1) [77–79]. Such viral infections can initiate a state of immune activation that persists long after the virus is cleared. This chronic inflammatory response not only damages the BBB but also increases its permeability, consequently contributing to the development of persistent ME/CFS symptoms. The recent evidence shows that the dUTPase protein encoded by EBV and HSV-1 can be transported to the brain via exosomes, where it induces pro-inflammatory cytokine release (e.g., IL-1β, IL-6, TNF-α) from endothelial cells, astrocytes, and pericytes, thereby degrading tight junction proteins, disrupting BBB integrity and inducing neuroinflammation [80].

Glial cell activation in ME/CFS: implications for neuroinflammation

Glial cells, particularly microglia and astrocytes, play a central role in the neuroinflammatory processes observed in ME/CFS. As the resident immune cells of the CNS, microglia are essential for immune surveillance and neural environment homeostasis. Evidence shows that microglia are chronically activated in ME/CFS [81]. Astrocytes are key in maintaining the BBB, blood flow, and neuronal metabolism [82, 83]. Increased BBB permeability allows inflammatory mediators enter the brain, triggering glial activation [84]. Upon activation, microglia release pro-inflammatory cytokines, thereby directly contributing to the development and persistence of neuroinflammation [85]. Elevated neuroinflammation disrupts neuronal activity, leading to cognitive dysfunction and fatigue in ME/CFS. A study demonstrated decreased levels of GSH, creatine, and myo-inositol in ME/CFS patients. Notably, the reduction in myo-inositol points to glial dysfunction, emphasizing the pathophysiological importance of glial cells in this disorder [86]. A meta-analysis of 65 neuroimaging studies on ME/CFS revealed hypoactivity in the insula and thalamus, thereby disrupting limbic connections and contributing to ME/CFS symptoms [87].

Crosstalk-driven vicious cycles: the interplay of oxidative stress, chronic inflammation, and mitochondrial impairment in ME/CFS

The oxidative stress-inflammation feedback loop in ME/CFS

Under normal physiological conditions, the immune system maintains the balance of ROS and RNS, which are important for cell signaling and effective immune responses [88, 89]. ME/CFS is characterized by a breakdown of this balance, resulting in persistent oxidative stress and chronic inflammation. Studies demonstrate that ROS can activate pro-inflammatory factors via pathways like mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [90–92]. ROS enhances inflammation by activating MAPK, which subsequently phosphorylates downstream proteins to upregulate the expression of pro-inflammatory genes such as IL-6, TNF-α, and IL-1β [90]. Similarly, ROS also enhance inflammation through NF-κB pathway activation, leading to IκB degradation, NF-κB nuclear translocation, and transcriptional upregulation of inflammatory mediators [93, 94]. In ME/CFS, elevated levels of oxidative stress markers have been linked to inflammatory cytokine production. Domingo et al. [95] reported that ME/CFS patients exhibited higher levels of fibroblast growth factor 21 and N-terminal prohormone of brain natriuretic peptide than healthy controls, along with elevated oxidative stress markers and increased inflammatory cytokines (IL-1β, IL-6, TNF-α, and C-reactive protein). He et al. [96] detected elevated levels of pro-inflammatory cytokines (IL-1β, IL-6) and oxidative stress markers (nitrotyrosine, 4-hydroxynonenal) in the cortical and hippocampal regions of a mouse model of ME/CFS. Collectively, these pro-inflammatory cytokines can further exacerbate oxidative stress, creating a self-perpetuating cycle that sustains inflammation and tissue damage.

Mitochondrial dysfunction and oxidative stress: a vicious cycle

In ME/CFS, elevated ROS and RNS levels are associated with mitochondrial dysfunction by damaging mtDNA and membranes, disrupting the ETC, and triggering mitophagy. The resulting oxidative stress impairs mitochondrial respiration, compromises ETC function, and increases membrane permeability, resulting in reduced ATP production and potential mitochondrial shutdown [97, 98]. Impaired mitochondria not only generate excess ROS but also compromise cellular antioxidant capacity, compounding the overall oxidative stress [64]. In ME/CFS, a self-perpetuating cycle exists between oxidative stress and mitochondrial dysfunction. Oxidative stress impairs mitochondrial integrity and disrupts ATP production, thereby causing energy deficiency and worsening fatigue. Concurrently, damaged mitochondria overproduce ROS, which subsequently intensifies oxidative stress and drives further mitochondrial impairment.

Building on the aforementioned insights, we proposed an integrative pathophysiological framework model of ME/CFS (Fig. 1). Inflammatory cytokines (such as IL-1β, IL-6, TNF-α, and IFN-γ) are central to the pathogenesis of ME/CFS. First, EBV and HSV-1 dUTPase enter the brain via exosomes, inducing endothelial cells, astrocytes, and pericytes to release inflammatory cytokines. Second, TNF-α amplifies inflammation by stimulating IL-1β and IL-6 production in a positive feedback loop. Third, increased inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α, and IFN-γ) disrupt BBB integrity and induce neuroinflammation. Fourth, these inflammatory cytokines elevate ROS/RNS levels, triggering oxidative stress that inflicts damage on mitochondrial DNA, membranes, and the ETC, ultimately culminating in ATP depletion. In turn, these compromised mitochondria produce excess ROS, which further stimulates pro-inflammatory gene expression through MAPK and NF-κB signaling, creating a self-reinforcing feedback loop that amplifies the inflammatory cytokines response. This process forms a self-sustaining pathological network, wherein inflammatory cytokines function as both initiators and products in a vicious cycle. The resulting state of chronic inflammation ultimately drives the clinical manifestation of muscle pain. Chronic bioenergetic failure, characterized by impaired oxidative phosphorylation and a persistent ATP deficit, may underlie the profound fatigue and PEM in ME/CFS. Simultaneously, persistent neuroinflammation and oxidative damage detrimentally contribute to cognitive impairment or “brain fog” in ME/CFS.

Fig. 1.

Integrative pathophysiological framework model of ME/CFS

Pharmacological and non-pharmacological interventions and management for ME/CFS

Potential therapeutic directions in immune modulation

Therapeutic application of intravenous immunoglobulin (IVIG) in ME/CFS

Immunoglobulin G (IgG) preparations confer broad-spectrum immunity against diverse bacterial and viral pathogens. Human IgG preparations are available as IVIG or subcutaneous immunoglobulin [99]. IVIG mediates its immunomodulatory action by suppressing autoantibody activity, modulating cytokine networks, inhibiting complement activation, and regulating Fc receptor expression on immune cells [100–102]. Clinical studies on the efficacy of IVIG in ME/CFS have yielded inconsistent results. Administration of low-dose subcutaneous Ig (0.06 g/kg/month for 5 weeks) in an uncontrolled case series (n = 17 with infection-related ME/CFS) yielded positive outcomes. There was a decline in composite symptom scores (81 to 63) alongside concurrent rises in quality of life (25 to 50) and working capacity (5 to 25) [103]. However, this double-blind, randomized, placebo-controlled trial assigned 99 CFS patients to monthly infusions of placebo or IVIG (0.5, 1, or 2 g/kg) for three months. Over a six-month period, comprehensive assessments were conducted covering clinical metrics (e.g., Karnofsky scale, quality-of-life visual analog scales, activity diaries), immunological markers (CD4/CD8 counts, delayed-type hypersensitivity), and adverse effects. The findings collectively indicated an absence of dose-dependent efficacy for IVIG in CFS, and did not support its use as a standard therapy for this condition [104]. In summary, IVIG is not a part of current clinical practice for ME/CFS, and the role of IVIG in ME/CFS remains to be defined through larger, more rigorous clinical trials.

Rintatolimod: toll-like receptor 3 (TLR3) agonist for ME/CFS therapy

By activating TLR3, rintatolimod triggers a type I interferon-mediated antiviral response, which upregulates effector proteins such as 2ʹ-5ʹ oligoadenylate synthetase and protein kinase R to degrade viral ribonucleic acid (RNA) and inhibit translation, collectively enhancing the host’s antiviral defense. A Phase III, double-blind, placebo-controlled, randomized, multi-center study involving 208 ME/CFS patients evaluated the efficacy of rintatolimod. The results showed that 51.2% of a severely debilitated patient subgroup (n = 21/41) experienced a ≥ 25% improvement in exercise treadmill test duration [105]. Another Phase III, double-blind, placebo-controlled trial with 234 severe CFS patients showed that rintatolimod yielded a 21.3% placebo-adjusted improvement in exercise tolerance by Week 40. In addition, patients receiving rintatolimod also demonstrated reductions in concomitant medication use and significant enhancements in Karnofsky Performance Scores and activities of daily living (ADL) compared to those on placebo [106]. However, it is important to note that rintatolimod has not been approved for marketing, and adverse events such as initial mild flu-like symptoms may occur. The interpretation of these findings requires caution, and further studies are essential to determine its broader translation and long-term safety.

Treatment strategies for antioxidant stress

N-acetylcysteine (NAC): a GSH precursor with antioxidant and immunomodulatory effects

As a precursor to GSH, NAC directly scavenges ROS and boosts GSH levels, thereby enhancing antioxidant capacity and mitigating oxidative stress [107]. Evidence indicates that NAC supplementation has been shown to elevate key antioxidant markers, including GSH, CAT, and total antioxidant capacity [108, 109]. Additionally, NAC also helps regulate glutamate homeostasis, reduce cytokines (such as IL-6, IL-1β, and TNF-α), and enhance mitochondrial function [110, 111]. A pilot study demonstrated GlyNAC (a combination of glycine and NAC) supplementation in older adults improved GSH, mitochondrial function and reduced oxidative stress, with notable benefits observed in cognitive and muscle function [112]. A study examined the impact of NAC (1,800 mg/day for 4 weeks) on cerebral GSH and clinical symptoms in 16 ME/CFS patients. The results indicated that NAC supplementation led to increased cortical GSH levels and a concurrent, significant reduction in ME/CFS symptoms as assessed by the CDC CFS symptom inventory [113]. Shankar et al. [64] investigated oxidative stress and mitochondrial function by employing flow cytometry, RNA-seq, and mass spectrometry on blood samples from 15 ME/CFS patients, 15 PACS patients, and 16 healthy controls. They found that NAC did not significantly reduce T-cell hyperproliferation in female patients with ME/CFS or PACS, suggesting that merely increasing GSH levels may be insufficient to address the underlying oxidative stress. Further large-scale clinical trials are warranted to comprehensively evaluate the therapeutic potential and safety of NAC in individuals with ME/CFS.

Coenzyme Q₁₀ (CoQ10): a mitochondrial antioxidant and immunomodulator in ME/CFS

CoQ10 functions as a powerful antioxidant by cycling between its oxidized and reduced forms, which allows it to scavenge ROS and thereby shield mitochondrial membranes and DNA from oxidative damage [114]. CoQ10 supplementation boosts antioxidant enzymes like SOD and CAT, reducing oxidative stress [115, 116]. As an indispensable component of the mitochondrial ETC, CoQ10 plays a central role in electron transfer, a process vital for oxidative phosphorylation and ATP generation [117]. CoQ10 supplementation restores mitochondrial electron flow, thereby increasing ATP production and consequently reducing oxidative stress in ME/CFS patients [118]. Additionally, CoQ10 demonstrates anti-inflammatory properties in ME/CFS through the suppression of pro-inflammatory cytokines like IL-6 and TNF-α, which helps mitigate systemic inflammation [115]. Studies suggest that CoQ10 supplementation can alleviate fatigue in ME/CFS patients, as evidenced by an 8-week trial where a combination of CoQ10 (400 mg) and selenium (200 µg) significantly reduced fatigue and improved quality of life [119]. A 12-week trial involving 207 ME/CFS patients found that supplementation with CoQ10 (200 mg) and nicotinamide adenine dinucleotide (20 mg) resulted in significant reductions in fatigue along with improvements in overall quality of life and sleep parameters [120]. Despite encouraging findings, rigorously designed, large-scale trials are needed to confirm the clinical benefits of CoQ10 for ME/CFS.

Therapeutic potential of molecular hydrogen (H₂) in ME/CFS

The small molecular size of H₂ enables it to penetrate biological membranes and neutralize ROS and RNS, such as hydroxyl radicals (·OH) and peroxynitrite, without disrupting beneficial signaling molecules such as hydrogen peroxide [121]. A potential benefit of H₂ therapy lies in its ability to mitigate the cellular burden of oxidative damage, which alleviates core symptoms such as fatigue, cognitive dysfunction, and muscle pain in ME/CFS. Mikami et al. [122] conducted a randomized, double-blind, placebo-controlled trial on healthy participants. Their results demonstrated that pre-exercise hydrogen water consumption not only improved endurance capacity but also significantly reduced subjective fatigue scores. Results of a systematic review and meta-analysis demonstrated that hydrogen supplementation significantly alleviated fatigue in healthy adults, with evidence of moderate certainty [123]. Friedberg and Choi [124] conducted a 28-day pilot randomized blinded trial in 23 ME/CFS patients and found that daily hydrogen water supplementation did not improve self-reported fatigue compared to placebo. Conversely, four ME/CFS patients receiving hydrogen gas inhalation (6–7%, 3–5 h/day) showed progressive symptom improvement over 20 weeks. Their total symptom scores decreased from 43 to 13 on the Canadian Consensus Criteria, accompanied by substantial alleviation of post-exertional fatigue and cognitive impairment [125]. The discrepancies across these studies may stem from differences in administration routes (inhaled vs. oral) and duration of intervention.

Potential role of nutritional and vitamin supplementation

Nutritional and vitamin supplementation has been explored as a potential therapeutic strategy for alleviating the symptoms of ME/CFS. Vitamin B12 is important for energy, nerve function, and the synthesis of erythrocyte. A cross-sectional survey of 38 ME/CFS patients receiving long-term B12 injections and oral folic acid demonstrated that higher injection frequencies and doses, combined with elevated daily folic acid intake, were associated with improved clinical outcomes [126]. In a 3-month open trial of vitamin B12 nasal drops involving 51 ME/CFS patients, 34 responders showed improved physical activity and fatigue scores, with these clinical benefits correlating with a marked increase in serum B12 levels from 328 pmol/L to 973 pmol/L [127].

Vitamin D is a fat-soluble vitamin that is essential for immune function and calcium and bone metabolism. Wepner et al. [128] demonstrated that neither 2,400 IU/week nor 1,200 IU/week of vitamin D3 supplementation effectively relieved pain in ME/CFS patients. Similarly, Witham et al. [129] also reported that high-dose vitamin D3 supplementation (100,000 IU every 2 months for 6 months) failed to improve vascular function markers or reduce fatigue in ME/CFS patients. Conversely, the coadministration of weekly high-dose vitamin D (cholecalciferol 50,000 IU) with antidepressant therapy was associated with significantly improved fatigue scores at weeks 4, 8, and 12 in a case-control study [130]. These findings collectively suggest that the greatest clinical benefit of vitamin D is likely achieved when it is used in combination with other therapies, rather than alone.

In a prospective study of 38 female CFS patients, 2 months of multivitamin-mineral supplementation resulted in increased SOD activity with concomitant alleviation of fatigue, sleep disturbances, autonomic symptoms, and headache burden [131]. Daily supplementation with a combination of yeast beta-glucan (250 mg), vitamin D3 (3.75 µg), vitamin B6 (1.05 mg), and zinc (7.5 mg) for 36 weeks was found to significantly alleviate cognitive fatigue in 65 ME/CFS patients, as evidenced by a randomized, double-blind, placebo-controlled trial [132]. Current evidence supports the view that strategies aimed at correcting multiple potential nutrient deficiencies simultaneously offer more substantial clinical benefits compared to isolated vitamin supplementation in ME/CFS.

Treatment strategies for mitochondrial dysfunction in ME/CFS

L-Carnitine: biological functions and therapeutic applications

L-carnitine is a naturally occurring amino acid derivative primarily synthesized in the liver and kidneys. It plays an essential role in transporting long-chain fatty acids into the mitochondrial matrix for β-oxidation, thereby supporting the TCA cycle and ATP production in energy metabolism. L-carnitine supports mitochondria by restoring mitochondrial membrane potential and enhancing respiratory function [133]. L-carnitine is an antioxidant that decreases acyl-CoA accumulation, and protects mitochondria and other cellular structures from oxidative damage [134]. Studies have identified low carnitine levels in ME/CFS patients, suggestive of underlying mitochondrial impairment [135]. L-carnitine emerged as one of the few dietary supplements showing significant efficacy in reducing fatigue in ME/CFS patients according to a systematic review, notwithstanding methodological limitations such as small sample size and potential selection bias [136]. The study reported that administration of oral L-carnitine was associated with restored serotonin levels and reduced fatigue in patients with ME/CFS and hypothyroidism [137]. Although preliminary evidence is encouraging, comprehensive studies are needed to definitively establish the therapeutic role of L-carnitine in ME/CFS and to optimize its clinical application.

Oxaloacetate supplementation

As a crucial intermediate in the TCA cycle, oxaloacetate is essential for aerobic energy production. It upregulates peroxisome proliferator-activated receptor gamma coactivator 1 alpha, the master regulator of mitochondrial biogenesis, which in turn stimulates mitochondrial proliferation [138]. Oxaloacetate holds potential to augment cellular energy production by promoting the biogenesis of mitochondria. ME/CFS patients exhibit dysregulated energy metabolism, which is characterized by impaired mitochondrial oxidative phosphorylation and altered substrate utilization [139]. Oxaloacetate supplementation helps restore the normal functioning of the TCA cycle and enhances cellular energy production, thereby alleviating fatigue symptoms. Clinical trials have demonstrated that 6-week oxaloacetate supplementation produces marked improvements in both physical and mental fatigue. Furthermore, a clear dose-response relationship was observed, wherein higher doses were associated with greater symptomatic relief [140]. Cash et al. [141] found that daily supplementation with 2,000 mg oxaloacetate for 3 month significantly reduced fatigue levels by over 25% from baseline compared to the rice flour placebo.

Sodium dichloroacetate (DCA)

An analysis of 200 ME/CFS patients and 102 healthy individuals revealed reduced amino acids involved in oxidative metabolism, indicative of PDH dysfunction [76]. PDKs normally inhibit PDH, shifting metabolism toward lactate production. By inhibiting PDK, DCA facilitates PDH-mediated conversion of pyruvate to acetyl-CoA, thus enhancing mitochondrial oxidative capacity and reducing lactate buildup [142]. A 30-day pilot trial of a sodium DCA-based nutritional supplement in 22 ME/CFS patients resulted in a 42.7% reduction in fatigue severity scores among 10 participants [143]. In a prospective trial of 35 patients with ME/CFS, a logistic regression analysis with stepwise elimination identified six pretreatment characteristics that accurately differentiated DCA responders from non-responders, with an ROC AUC of 0.92 [144]. In another study, DCA administration rescued locomotor deficits and elevated PDH activity in mice with ME/CFS-like manifestations induced by a 25-day repeated forced swimming test [145]. As mentioned above, DCA holds promise for alleviating symptoms like fatigue in certain ME/CFS patients. However, its therapeutic effects exhibit considerable heterogeneity, and its safety profile and overall applicability require further validation.

Treatment and management of neuroinflammation

Low-dose naltrexone (LDN)

As a potent antagonist of central µ-opioid receptors (µOR), naltrexone at low doses (LDN, 3–5 mg) acts through the blockade of these receptors to consequently reverse their inhibition of transient receptor potential cation channel subfamily M member 3 (TRPM3). In ME/CFS patients, dysfunction of the TRPM3 calcium channel, which is critical for calcium permeability and NK cell function, results in diminished NK cell activity and disrupted calcium signaling [146]. Through its blockade of µOR, LDN facilitates the restoration of TRPM3 activity and the subsequent normalization of calcium influx in NK cells [146, 147]. Eaton-Fitch et al. [148] identified a reduction of calcium influx in ME/CFS patients, which was restored by naltrexone. Additionally, by blocking Toll-like receptor 4, naltrexone may also alleviate neuroinflammation in ME/CFS [149]. Experimental study demonstrates that LDN induces a phenotypic shift in BV-2 microglial cells, transitioning them from a pro-inflammatory(iNOS^highCD206^low) to a quiescent, anti-inflammatory M2 state (iNOS^lowCD206^high) [150]. In a study of 218 ME/CFS patients, LDN demonstrated a significant improvement in 73.9% of cases, with notable benefits in alertness and overall function [151].

Minocycline

Minocycline, a tetracycline antibiotic, can penetrate the BBB, inhibit the M1-type (pro-inflammatory) polarization of microglia, and attenuate the microglial expression and release of pro-inflammatory factors such as IL-1β, IL-18, and TNF-α [152–154]. A preclinical study demonstrated that minocycline pretreatment significantly suppressed inflammatory microglial activation, alleviated pain, and restored locomotor function [155]. Following a regimen of 100 mg twice on the first day and then 100 mg daily for 41 days, oral minocycline demonstrated improvement in ME/CFS symptoms including disequilibrium, orthostatic intolerance, and neuropathic pain, with the most pronounced effects observed in early-stage patients [156]. The antioxidant properties of minocycline help protect neurons from mitochondrial DNA damage and GSH depletion [157]. In a pilot study of 55 ME/CFS patients, a 41-day course of oral minocycline (100 mg/day after a loading dose) resulted in favorable symptom improvements for 80% of treatment completers, reflected in better performance status and ADL scores, with a notably higher success rate (90%) observed when treatment was initiated within six months of onset [158].

Non-pharmacological interventions and management for ME/CFS

Cognitive behavioral therapy (CBT)

Grounded in the biopsychosocial model, CBT facilitates the targeted modification of dysfunctional beliefs, avoidance behaviors, and maladaptive coping strategies [159]. Fear avoidance beliefs are theorized to serve as a mediator between avoidance behaviors and subsequent issues such as fatigue and social impairment. CBT addresses this by helping patients develop adaptive coping mechanisms, thereby reducing avoidance, alleviating fatigue, and enhancing social engagement [160]. A pooled analysis of 1,298 ME/CFS patients from eight trials revealed that CBT was associated with significant reductions in fatigue severity and functional impairment, alongside improvements in physical function [160]. Research shows that internet-based CBT has been shown to mitigate fatigue and slow illness progression in adolescents with ME/CFS [161]. A meta-analysis of 15 randomized controlled trials (RCTs) revealed that CBT effectively relieved fatigue, depression, and anxiety, with long-term improvements and high adherence [162]. Furthermore, a resting-state fMRI study involving 72 ME/CFS patients revealed that baseline fatigue levels were associated with heightened connectivity between the somatomotor network (SMN) and premotor network, along with weakened connectivity between the SMN and the default mode network [163].

Graded exercise therapy (GET)

GET is a structured intervention method whose core principle is the gradual progression of activity levels, aimed at reversing deconditioning and building physical capacity [164]. Research on GET for ME/CFS has reported divergent outcomes. Although some trials documented GET related fatigue improvement [165, 166], recent findings associated GET with symptom exacerbation, marked by increased fatigue, pain, and PEM in a significant proportion of patients [167]. A pragmatic trial was conducted to compare GET and activity management in 241 adolescents (aged 8–17) with mild to moderate ME/CFS. No significant inter-group difference was observed with regard to the primary outcome (physical function on the Short-Form 36 subscale at 6 months) [168].

The controversy surrounding CBT and GET for ME/CFS arises from fundamental methodological flaws, including selective reporting, poor control group design, and reliance on subjective primary outcomes in nonblinded studies and other methodological concerns [169]. Critics argue that trials supporting CBT and GET are heavily reliant on subjective outcomes (e.g., self-reported fatigue and physical function), resulting in highly inconsistent recovery rates (7%–69%) that are determined by arbitrary thresholds. When evaluation of objective measures, including work rehabilitation, physical fitness, and activity levels, CBT and GET seem to have minimal or no efficacy [170]. The updated NICE guidelines classify GET as harmful and expressly advise against its use, while repositioning CBT as an adjunctive rather than a curative treatment [171].

Energy management and activity pacing for ME/CFS

Energy management and activity pacing are widely recognized as first-line approaches for managing ME/CFS, particularly following the 2021 update of NICE guidelines, which recommended activity pacing as the only management strategy for ME/CFS [172]. These strategies are grounded in the energy envelope theory, whose conceptual foundation is the maintenance of a balance between activity and rest to prevent energy depletion. The energy envelope model postulates that patients achieve optimal outcomes when there is a close alignment between energy expenditure and perceived available energy, resulting in enhanced physical function and reduced fatigue.

In practice, activity pacing is guided by several key principles: (i) Understanding Energy Limits: Patients learn to recognize their personal energy thresholds, identify early signs of overexertion, and abstain from activities that exceed these limits [173]. (ii) Use of Activity Diaries or Self-Monitoring Tools: Systematic tracking of daily activities, symptoms, and energy levels using activity diaries or self-monitoring tools helps decision-making regarding when to rest and when to engage in activity [173]. (iii) Personalized Planning Within the Energy Envelope: Pacing encourages adjusting daily routines based on current symptoms and available energy rather than following fixed schedules. Daily routines are adjusted based on symptom fluctuation, with pacing strategies personalized to each patient’s abilities, preferences, and lifestyle [174]. Figure 2 presents a summary of care pathway for pacing, and it encompasses practical suggestions for consultations, methods for tracking patient progress, and a list of red flags signaling health deterioration.

Fig. 2.

ME/CFS pacing care pathway

A scoping review on pacing as a a strategy for managing ME/CFS found that 11 of the 17 included studies reported benefits from activity pacing [173]. A systematic review and meta-analysis demonstrated that pacing interventions lead to a significant reduction in fatigue (Hedges’ g = -0.52) and an improvement in physical function among ME/CFS patients compared to no treatment or routine care [175]. Overall, energy management and activity pacing, which are grounded in the principles of the energy envelope model, constitute essential, evidence-based components of ME/CFS care.

Management with TCM for ME/CFS

TCM has been increasingly explored as an alternative approach to managing ME/CFS [176]. Acupuncture shows potential in ME/CFS management through its ability to activate the vagus nerve, reduce pro-inflammatory cytokines, polarize immune cells toward an anti-inflammatory state, and inhibit critical inflammatory signaling pathways [177, 178]. In animal models, acupuncture has an antioxidant effect by elevating the activity of enzymes such as SOD, GSH peroxidase, and CAT, and suppressing pro-oxidant markers including malondialdehyde and ROS [179, 180]. A study involving 290 ME/CFS patients demonstrated that an 8-week intervention combining ginger-indirect moxibustion with acupuncture produced considerable improvements [181]. Another meta-analysis of 16 studies, encompassing 1,346 participants confirmed that manual and electroacupuncture are effective in alleviating symptoms associated with ME/CFS [182].

Herbal formulas may reduce fatigue and improve quality of life by modulating immunity, regulating metabolism, enhancing antioxidants, or altering gut microbiota. A study revealed that Young Yum Pill reversed metabolic disturbances by increasing glycogen storage, enhancing antioxidant enzyme activity (superoxide dismutase), and reducing serum triglyceride, lactic acid, and urea nitrogen levels [183]. In a randomized, double-blind, placebo-controlled trial involving 127 ME/CFS patients, administration of Sijunzi Decoction demonstrated significant efficacy, as evidenced by reduced Chalder Fatigue Questionnaire (CFQ) scores and measurable alterations in gut microbiota composition [184]. Zhang et al. [182] conducted a review of 84 RCTs involving 6,944 participants and concluded that Chinese herbal medicine significantly reduced fatigue scores and improved clinical outcomes. Another meta-analysis of 6 RCTs (n = 623) demonstrated that the addition of Xiaoyao San to standard biomedical treatments yielded superior clinical effectiveness and a favorable safety profile [185]. However, these findings should be cautiously interpreted, as the available evidence is constrained by methodological limitations. Further rigorously designed RCTs are required to conclusively establish both efficacy and safety.

Comprehensive clinical assessment and management of ME/CFS based on symptoms

Fatigue and PEM

Fatigue and PEM constitute the hallmark features of ME/CFS. Their clinical assessment relies on a combination of objective metrics and subjective measures, with self-report instruments such as the Fatigue Severity Scale and the CFQ being readily available and straightforward to administer. However, these measures are susceptible to interpretive bias and fail to accurately capture dynamic fatigue states, which may undermine data reliability [186, 187]. Comprehensive tools, such as the Checklist Individual Strength and the Multidimensional Fatigue Inventory assess multiple aspects of fatigue, while their administration is often time-consuming. The DePaul Symptom Questionnaire (DSQ) is designed to systematically track the frequency, triggers, and recovery patterns of PEM. Muscle strength was objectively quantified using the hand grip strength test, whereas fatigue severity and its impact on daily life were subjectively assessed via the Patient-Reported Outcomes Measurement Information System Fatigue Computer-Adaptive Test [188, 189]. Cardiopulmonary Exercise Testing enables a comprehensive evaluation of functional exercise capacity by quantitatively measuring the body’s physiological responses to exertion [190].

The strategies for managing fatigue and PEM mainly focus on symptom relief and functional improvement. Pharmacological treatments can help alleviate fatigue and PEM, but their use is often accompanied by drawbacks such as insomnia, nausea, and the risk of dependence. Supplementation with nutrients like L-carnitine and CoQ10 may improve energy production. The CBT may provide benefit for a subset of ME/CFS patients who present with maladaptive thoughts and behaviors [191]. Activity pacing helps patients prevent overexertion and manage energy efficiently [192]. Mindful movement practices such as yoga and Tai Chi help reduce stress and improve physical well-being. All the assessment tools and management methods for fatigue and PEM are summarized in Table 2.

Table 2.

Summary of fatigue and PEM assessment and management in ME/CFS

Assessment /management	Tool	Description	Strengths	Limitations
Assessment	Fatigue Severity Scale	The Fatigue Severity Scale is a 9-item self-report questionnaire designed to measure fatigue severity and its impact on daily functioning. It is widely used in ME/CFS and other chronic illnesses.	Quick and easy to use.	Subjective, influenced by personal interpretation of fatigue. Does not assess fluctuations in fatigue.
	Chalder Fatigue Scale	The Chalder Fatigue Scale consists of 14 items assessing the frequency and severity of fatigue. It evaluates both physical and mental fatigue.	Focuses on frequency and severity.	The Chalder Fatigue Scale has limitations in comprehensiveness.
	Checklist Individual Strength	The Checklist Individual Strength is a comprehensive 20-item tool assessing fatigue across 4 domains: fatigue severity, physical functioning, concentration, and motivation. It is widely used for chronic illness.	Multidimensional, assessing fatigue’s impact on physical and cognitive aspects.	Relatively long. Focuses on subjective experiences and does not assess objective functioning.
	Multidimensional Fatigue Inventory	The Multidimensional Fatigue Inventory measures fatigue across 5 dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue.	Comprehensive, capturing various dimensions of fatigue.	Lengthy and time-consuming.
	CDC Symptom Inventory	The CDC Symptom Inventory is a self-report questionnaire designed by the CDC about physical symptoms during the past month.	Widely used for ME/CFS diagnosis and research.	Focuses on symptom presence, frequency, and intensity rather than fatigue impact on daily life.
	FIS	The FIS measures the impact of fatigue on daily life, including physical, psychosocial, and cognitive functioning.	Measures functional impact of fatigue, not just severity.	Lengthy.
	PROMIS Fatigue Computer-Adaptive Test	The PROMIS Fatigue Computer-Adaptive Test is a computer-adaptive test that evaluates the experience of fatigue (e.g., frequency, duration, intensity) and its impact using dynamic, real-time adaptive questioning based on the patient’s responses.	Tailored and efficient, reducing patient burden.	Requires computer access and internet connectivity.
	Cardiopulmonary Exercise Testing	Cardiopulmonary Exercise Testing measures objective exertional or functional capacity by assessing variables such as oxygen consumption, HRV, and ventilatory efficiency during graded exercise.	Objective assessment of integrative exercise responses involving the pulmonary, cardiovascular and skeletal muscle systems.	Expensive and requires specialized equipment.
	Hand Grip Strength	Hand Grip Strength is a simple, objective measure of muscle strength and endurance. It is often used as a functional marker of general physical capacity and fatigue.	Objective, non-invasive measure of muscle strength.	Does not directly assess fatigue itself, but rather muscle function. Can not capture neurological or cognitive aspects of fatigue.
	DSQ	Self-report tool with PEM-specific items (frequency, triggers, recovery).	High sensitivity	Subjectivity. Relies on recall accuracy.
Management	Pharmacological Interventions	Pharmacological agents aim to address fatigue and PEM.	Can address comorbid symptoms.	Side effects (e.g., insomnia, nausea, dependence).
	CBT	A psychological therapy focusing on changing dysfunctional beliefs and behaviors that may contribute to fatigue.	Reduces the psychological burden of fatigue.	Effectiveness may vary by patients.
	Pacing	Pacing involves balancing activity and rest, allowing patients to manage energy expenditure to avoid overexertion and worsening fatigue.	Personalized and non-invasive approach. Helps to prevent overexertion, thus minimizing PEM.	Requires self-discipline and accurate self-monitoring of energy levels. May not be effective for those with severe ME/CFS symptoms.
	Nutritional Interventions	Use of supplements (e.g., Coenzyme Q10, L-carnitine) to address fatigue	May improve mitochondrial function and energy production.	Evidence is inconsistent. Adverse effects reported.
	Mindful Movement (Yoga/Tai Chi/Qigong)	Mindful movement practices such as yoga, Tai Chi, and Qigong involve gentle movements, breathing exercises, and meditation, designed to reduce fatigue, improve flexibility, and enhance relaxation.	Enhances physical mobility and flexibility. Improves mental well-being by reducing stress and promoting mind-body balance.	May not directly target the physiological causes of fatigue but rather mitigates its effects.

CDC: Centers for Disease Control and Prevention; ME/CFS: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; FIS: Fatigue Impact Scale; PROMIS: Patient-Reported Outcomes Measurement Information Systems; DSQ: DePaul Symptom Questionnaire; CBT: Cognitive Behavioral Therapy; PEM: post-exertional malaise

Sleep disturbances

Sleep disturbances in ME/CFS are characterized by nonrestorative sleep. A multimodal assessment approach is typically employed, encompassing patient-reported outcomes and objective monitoring. The Pittsburgh Sleep Quality Index (PSQI) is widely used to assess overall sleep quality, sleep disturbances, and daytime dysfunction [193]. Epworth Sleepiness Scale quantifies daytime sleepiness, complementing the clinical assessment of fatigue severity. Sleep diaries provide valuable longitudinal data on sleep patterns and help identify trends and potential triggers, whereas their accuracy is inherently dependent on patient or caregiver perception. Actigraphy enables continuous sleep-wake monitoring in home settings, but it may misclassify quiet wakefulness as sleep. Polysomnography is the gold standard for diagnosing sleep disorders [194], though it requires overnight stays, making it expensive and time-consuming.

Self-management strategies, such as implementing consistent sleep schedules, optimizing sleep environments, and employing relaxation techniques, can effectively enhance sleep quality [195]. CBT for insomnia is widely recognized as an effective first-line treatment for insomnia in patients with mental disorders and comorbid insomnia [196]. Furthermore, techniques such as progressive muscle relaxation, mindfulness, and guided imagery have been shown to effectively alleviate anxiety and promote psychophysiological relaxation. Pharmacological management should be used cautiously, especially over the long term [197]. All the assessment tools and management methods for sleep disturbances are displayed in Table 3.

Table 3.

Summary of sleep disturbances assessment and management in ME/CFS

Assessment/management	Tool	Description	Strengths	Limitations
Assessment	PSQI	A self-reported questionnaire assessing overall sleep quality, disturbances, and daytime dysfunction over the last month.	Provides a comprehensive measure of sleep quality, including sleep latency, duration, efficiency, and disturbances.	Influenced by anxiety and depression.
	ESS	A questionnaire that assesses daytime sleepiness by asking how likely the patient is to doze off during various activities.	Simple to administer and widely used for assessing sleepiness levels.	Influenced by anxiety and depression.
	Sleep Diaries	A tool where patients record their sleep patterns daily, including sleep onset, wake times, and any disturbances.	Provides a detailed record of sleep habits and patterns over time, helping identify trends and triggers for sleep disturbances.	Sleep diaries rely on patient or caregiver perception.
	Actigraphy	A wrist-worn device that continuously monitors sleep-wake cycles and movement patterns to assess sleep quality.	Provides objective, continuous monitoring of sleep patterns, including restlessness or fragmented sleep.	May misclassify quiet wakefulness as sleep.
	PSG	A comprehensive overnight sleep study that records brain waves, oxygen levels, heart rate, and muscle activity.	Considered the gold standard for diagnosing sleep disorders.	Requires overnight hospital stay or sleep clinic visit. Expensive and time-consuming.
Management	Cognitive Behavioral Therapy for Insomnia	A structured psychological treatment designed to change thoughts and behaviors contributing to insomnia.	Suitable for diverse patient groups.	There are barriers to its implementation include limited access, lack of knowledge, treatment beliefs, and insufficient availability in routine healthcare settings.
	Relaxation Techniques	Techniques such as progressive muscle relaxation, mindfulness, and guided imagery to reduce stress.	Reduces anxiety and promotes relaxation, which can lead to improved sleep quality.	Must be practiced regularly and may take time to achieve noticeable results.
	Pharmacological management	Pharmacologic treatment is a common approach for insomnia.	Pharmacologic treatment maybe help fall asleep easy or stay asleep long.	May cause mild side effects like dizziness or grogginess, and its long-term use should be approached with caution.

PSQI: Pittsburgh Sleep Quality Index; ESS: Epworth Sleepiness Scale; PSG: Polysomnography

Cognitive impairment

The cognitive impairment in ME/CFS, commonly known as “brain fog,” encompasses a range of deficits including decreased attention, reduced information processing speed, and impaired working memory [4, 198]. The Mini-Mental State Examination (MMSE) is a quick screening tool but has limited sensitivity for mild impairment. In contrast, the Montreal Cognitive Assessment (MoCA) offers greater sensitivity, though its results are influenced by the patient’s education level. The Cognitive Failures Questionnaire measures everyday cognitive lapses by self-report. Specialized tests such as CogState, Trail Making Test, and Continuous Performance Test offer in-depth assessments of attention, processing speed, and executive function. However, their results can be confounded by non-cognitive factors, including motor speed, visual ability, and color vision.

CBT has shown some promise in managing the cognitive complaints associated with ME/CFS, while the overall evidence regarding its efficacy remains limited and inconclusive. Cognitive training and rehabilitation programs, which target specific deficits in memory, attention, and executive function, have shown beneficial effects for individuals with ME/CFS. Activity pacing and energy conservation techniques enable patients to alleviate their cognitive fatigue and prevent the exacerbation of cognitive symptoms. Pharmacological options such as stimulants and antidepressants may be used alongside non-pharmacological interventions to address cognitive symptoms. The long-term efficacy of these medications for ME/CFS remains uncertain, and they may be associated with adverse effects. All the assessment tools and management methods for cognitive impairment are presented in Table 4.

Table 4.

Summary of cognitive impairment assessment and management in ME/CFS

Assessment/management	Tool	Description	Strengths	Limitations
Assessment	MMSE	A widely used, simple screening tool to assess cognitive impairment, focusing on orientation, attention, memory, language, and constructional ability.	Simple, fast, and reliable for screening cognitive impairment, widely used in clinical settings.	Less sensitive to mild impairment.
	MoCA	A brief cognitive screening tool designed to assess a wide range of cognitive abilities, including attention, memory, and executive function.	Quick and easy to administer. More sensitive than MMSE for mild cognitive impairment.	May be influenced by education level.
	Cognitive Failures Questionnaire	Self-report inventory assessing everyday cognitive lapses (memory, perception, motor function) on a frequency scale.	Quick, easy to administer.	Relies on self-reported data, which maybe influenced by mood and personal awareness.
	CogState	A computerized assessment tool that measures cognitive performance in areas such as attention, processing speed, and working memory.	Objective, remote administration possible.	Requires specialized equipment and trained personnel for administration. It may not be suitable for all clinical settings.
	TMT	A neuropsychological test used to assess attention and task switching abilities, part of executive function evaluation.	Provides insight into executive function and cognitive flexibility, useful in detecting attentional and task-switching difficulties.	Influenced by motor speed and visual ability, limited domain coverage.
	CPT	A test used to assess attention and working memory by measuring sustained attention and the ability to inhibit non-targets responses.	Objective and quantifiable measure of attention and response inhibition, widely used in research on cognitive deficits.	May be affected by fatigue or motivation.
	Stroop Color and Word Test	A neuropsychological test used to measure cognitive interference, where participants must name the color of the word, ignoring the word’s meaning.	Measures selective attention, cognitive flexibility, and inhibition, providing insights into the participant’s ability to manage cognitive interference.	Performance affected by reading speed and color vision.
Management	CBT	An intervention targeting maladaptive thoughts and behaviors to improve coping and reduce symptoms.	Reduces cognitive complaints in ME/CFS.	Controversial efficacy.
	Cognitive Training and Rehabilitation	Training and rehabilitation techniques that focus on improving memory, attention, and executive function through structured exercises.	Cognitive training can improve working memory, executive function and learning memory.	Cognitive training may be time-consuming and its effectiveness is highly individualized.
	Pacing and Energy Conservation	Managing cognitive load and energy, pacing activities to avoid overexertion, helping reduce cognitive fatigue.	Pacing helps avoid cognitive overload and fatigue, leading to improved performance and quality of life.	Limited research as a standalone intervention.
	Pharmacological Interventions	Use of medications to manage cognitive symptoms or slow decline.	Some efficacy in mild cognitive impairment and dementia.	Pharmacological treatments may have side effects, and long-term effectiveness is still under investigation in ME/CFS patients.

MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive Assessment; TMT: Trail Making Test; CPT: Continuous Performance Test; CBT: Cognitive Behavioral Therapy; ME/CFS: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Autonomic dysfunction

Autonomic dysfunction in ME/CFS manifests through diverse symptoms, primarily encompassing neurocardiovascular issues like orthostatic intolerance and postural orthostatic tachycardia syndrome (POTS), as well as neurogastrointestinal disturbances [199]. A range of assessment tools are employed to evaluate autonomic dysfunction, including Heart Rate Variability (HRV) analysis, the Composite Autonomic Symptom Scale (COMPASS), the DSQ, the Head-Up Tilt Table Test (HUTT), and the Active Stand Test. HRV serves as a non-invasive measure of autonomic nervous system function, but its utility is limited by sensitivity to external influences [200]. COMPASS and DSQ are designed to assess autonomic symptoms, but their reliance on subjective reporting is a methodological consideration. HUTT is considered as the gold standard for diagnosing orthostatic intolerance, it necessitates specialized clinical resources and may not fully reflect the patient’s symptom variability in daily life [201]. AST serves as a simple, quick, and low-cost screening method, while it may lack the sensitivity to detect transient or subtle autonomic abnormalities.

The management of autonomic dysfunction in ME/CFS incorporates a multi-modal approach, including fluid/salt intake, compression garments, GET, and targeted pharmacotherapy. The primary goal of fluid and salt supplementation is to elevate blood volume, thereby reducing orthostatic hypotension. Nevertheless, this intervention may prove insufficient in severe autonomic dysfunction and requires careful monitoring to avoid the development of hypertension. The use of compression garments improves circulatory support but may cause discomfort. In clinical practice, physical therapy and exercise are prescribed to improve cardiovascular stability, and their regimens must be individualized to avoid overexertion. Pharmacological interventions, including midodrine for hypotension, fludrocortisone for blood volume expansion, and beta-blockers for heart rate regulation, can provide relief from autonomic symptoms. However, they necessitate careful clinical monitoring due to potential side effects [2, 202]. The assessment tools and management methods for autonomic dysfunction are shown in Table 5.

Table 5.

Summary of autonomic dysfunction assessment and management in ME/CFS

Assessment /management	Tool	Description	Strengths	Limitations
Assessment	HRV Analysis	Non-invasive measurement of beat-to-beat heart rate fluctuations reflecting autonomic nervous system balance.	Objective. Correlates with fatigue severity and autonomic dysfunction.	Requires specialized equipment and analysis software. Results can be influenced by external factors.
	COMPASS	A comprehensive self-reported questionnaire assessing the severity of autonomic symptoms across multiple domains, including cardiovascular, vasomotor, secretomotor, gastrointestinal, and genitourinary systems.	Easy to administer. Covers broad symptom spectrum.	Subjective. Relies on patient self-report, which can be influenced by mood, awareness, or subjective interpretation of symptoms.
	DSQ	A comprehensive self-report questionnaire.	Provides a broad, validated assessment of ME/CFS symptom severity, including autonomic dysfunction.	It relies on patient self-report, which can be subjective and influenced by cognitive fatigue.
	HUTT	A test that involves tilting the patient to an upright position while monitoring cardiovascular responses.	Gold standard for diagnosing orthostatic intolerance.	Requires specialized equipment and trained personnel. May not capture daily symptom variability.
	AST	A test where the patient is asked to stand up while monitoring heart rate and blood pressure responses to assess orthostatic hypotension and autonomic dysfunction.	Simple, quick, and low-cost.	May not detect subtle autonomic dysfunctions and can be influenced by other factors.
Management	Fluid and Salt Supplementation	Increasing fluid intake and salt consumption to improve blood volume and counteract orthostatic hypotension and dizziness.	Fluid and salt management can help improve blood volume and reduce symptoms of orthostatic hypotension.	May not be sufficient for severe cases. Risk of hypertension.
	Compression Garments	Wearing compression stockings or abdominal binders to improve blood circulation and prevent blood pooling in the lower extremities.	Non-invasive. Can be used with other therapies.	Compression garments may cause discomfort.
	Physical Therapy and Exercise	A combination of gentle exercises and gradual increases in physical activity to enhance cardiovascular stability and autonomic regulation.	Improving cardiovascular function and reducing autonomic instability.	Overexertion can worsen symptoms.
	Pharmacological Treatments	Includes medications like midodrine (for hypotension), fludrocortisone (for blood volume), and beta-blockers (to regulate heart rate).	Pharmacological treatments can relief orthostatic hypotension and other autonomic dysfunctions symptoms.	Medications may have side effects.

HRV: Heart Rate Variability; COMPASS: Composite Autonomic Symptom Scale; DSQ: DePaul Symptom Questionnaire; HUTT: Head-Up Tilt Table Test; AST: Active Stand Test

Future research directions and perspectives on ME/CFS

Supplementary material 1 presents a summary of relevant ME/CFS clinical trials registered on ClinicalTrials.gov and the Chinese Clinical Trial Register (ChiCTR) over the past three years. A broad spectrum of interventions for ME/CFS has been investigated, encompassing pharmacological options such as rituximab, rapamycin, and lumbrokinase, as well as non-pharmacological approaches including yoga, CBT, and acupuncture. To advance the field, future research should prioritize refining therapeutic strategies, elucidating mechanisms, and developing personalized treatment approaches.

Personalized treatment approaches: targeting individual responses

The Hydrogen Water Intervention trial (NCT07009691) investigates hydrogen water as a potential supplemental therapy for ME/CFS symptoms. This study employs HRV monitoring to predict individual treatment responses and facilitate therapy personalization. The clinical trial (NCT06952413) evaluates rituximab for ME/CFS, specifically targeting underlying immune dysfunction, B cell abnormalities, and autoimmune components. Given the established role of immune dysfunction (including inflammatory cytokines, neuroinflammation, and immune cell abnormalities) in ME/CFS progression, the Low-dose Naltrexone for Post-COVID Fatigue Syndrome trial (NCT05430152) is currently exploring LDN’s potential to reduce both fatigue and inflammation, thus providing a mechanistically grounded therapeutic approach. The integration of large-scale multiomics with machine learning holds the key to the future of personalized medicine. This approach will enable the construction of predictive algorithms that can accurately forecast individual responses to therapy, thereby paving the way for precisely tailored treatment recommendations.

Mechanistic exploration and disease subtypes: unraveling the pathophysiology of ME/CFS

Although immune dysregulation, oxidative stress, and mitochondrial dysfunction are recognized as central to ME/CFS pathophysiology, a comprehensive understanding of their interplay and overall mechanistic integration continues to represent a critical direction for future research. The T cell dysfunction in ME/CFS trial (NCT06731179) utilizes T cell assays to assess immune dysfunction, focusing on T cell subfractions and their pathogenic role. The findings could help elucidate the established link between infectious triggers like COVID-19 and EBV and the development of ME/CFS. Current evidence indicates that ME/CFS patients exhibit significant alterations in T cell metabolism and function, characterized by mitochondrial dysfunction, reduced glycolytic activity, and upregulation of exhaustion markers [53, 203, 204]. The Brain-Gut Interaction Mechanism in CFS study (ChiCTR2200056530) employs fMRI and 16 S rRNA sequencing to elucidate the underlying interactions among immune, neuroinflammatory, and metabolic dysfunction. Emerging research indicates that ME/CFS patients frequently experience gut dysbiosis, consistently characterized by diminished microbial diversity and a specific depletion of health-promoting Firmicutes and butyrate-producing species [205, 206]. The identification of distinct microbiome-associated subtypes in ME/CFS should be a focus of future research, as it may facilitate the development of targeted microbial interventions including probiotics, prebiotics, dietary strategies, and fecal microbiota transplantation.

Innovative therapies and non-pharmacological interventions: a multidimensional approach

Non-pharmacological interventions have gained growing recognition in ME/CFS management as complementary approaches to pharmacological treatments. The Effectiveness of a Therapeutic Yoga Program on Fatigue (NCT06978582) evaluates the efficacy of yoga, breathing exercises, and body awareness in reducing fatigue, with HRV and the Chalder Fatigue Scale as primary assessments. As a mind-body practice, yoga improves physical flexibility and strength, decreases stress and anxiety levels, thus supporting emotional and cognitive regulation. Studies show that yoga can significantly reduce fatigue levels, pain, anxiety, depression, and improves subjective well-being and personality in ME/CFS patients [207, 208]. Transcutaneous vagus nerve stimulation (tVNS), an emerging non-pharmacological intervention targeting neuroinflammation and autonomic dysfunction, is presently under investigation in two registered clinical trials (NCT06585254 and NCT06170645). By modulating vagus nerve activity, tVNS mitigates cognitive deficits, improve autonomic function (e.g., HRV), and reduce POTS-related symptoms [209]. Future research should aim to optimize tVNS protocols by standardizing key parameters such as intensity, frequency, and duration.

Integrating real-world data (RWD) and digital health technologies (DHTs) for precise monitoring and management of ME/CFS

DHTs like wearables, mobile apps, and electronic health records facilitate the collection of multidimensional data on physiological, behavioral, and clinical symptoms, thereby enabling an integrated perspective of patient health status and disease progression [210]. RWD from diverse populations generates evidence that is complementary to RCTs, offering broader generalizability for clinical decision-making in real-world settings [211]. By combining RWD with DHTs, healthcare is undergoing a significant transformation, allowing for continuous, multidimensional patient monitoring and paving the way for precisely personalized interventions. The Solve Together platform (NCT04806620) collects multidimensional phenotypic data from electronic medical records, patient-reported outcomes, and wearable devices. This integrative approach facilitates the identification of disease endotypes, enables monitoring of ME/CFS progression, and supports the quantification of intervention efficacy. The Long COVID-19 Wearable Device Study (NCT05741112) employs continuous monitoring of sleep, activity, heart rate, and HRV in order to objectively quantify symptoms including PEM and fatigue severity. By integrating photobiomodulation and biofeedback with remote monitoring platforms, ongoing CFS trials (NCT06145867, NCT05397626) seek to enhance patient engagement and adherence, thereby potentially improving treatment outcomes. The Multi-Center Registry for ME/CFS (NCT05778006) develops a large-scale registry to standardize the collection of epidemiological data, facilitate phenotypic stratification, and monitor longitudinal outcomes. Therefore, future research should prioritize: (i) establishing rigorously validated digital biomarkers to enable objective and real-time monitoring of disease status, such as indicators of autonomic dysfunction linked to PEM; (ii) applying machine learning models to analyze diverse RWD streams for delineating disease endotypes and predicting individual responses to therapies.

Conclusions

This review elucidates the intricate biological basis of ME/CFS, affirming its status as a complex, heterogeneous disorder that necessitates an interdisciplinary approach. By synthesizing current evidence, we identify promising research directions for developing targeted, personalized treatment strategies. Promising drug therapies such as IVIG, rintatolimod, antioxidants, and mitochondrial-targeting agents combined with non-pharmacological approaches like CBT, activity pacing, and TCM, offer a spectrum of supportive options for personalized ME/CFS management. It should be noted that CBT serves in an adjunctive capacity, while GET is not recommended due to its potential for harm. However, the individual differences of ME/CFS necessitate further research into biomarker discovery, underlying mechanism, and the development of precisely targeted interventions.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

ADL

Activities of daily living

ATP

Adenosine triphosphate

BBB

Blood-brain barrier

CAT

Catalase

CBT

Cognitive behavioral therapy

CDC

Centers for Disease Control and Prevention

CFQ

Chalder Fatigue Questionnaire

ChiCTR

Chinese Clinical Trial Register

CNS

Central nervous system

COMPASS

Composite Autonomic Symptom Scale

CoQ₁₀

Coenzyme Q₁₀

DCA

Sodium dichloroacetate

DHTs

Digital health technologies

DSQ

DePaul Symptom Questionnaire

EBV

Epstein-Barr virus

ETC

Electron transport chain

FIS

Fatigue Impact Scale

fMRI

Functional magnetic resonance imaging

GET

Graded exercise therapy

GPx

Glutathione peroxidase

GSH

Glutathione

H₂

Molecular hydrogen

HRV

Heart rate variability

HSV-1

Herpes simplex virus

HUTT

Head-Up Tilt Table Test

IFN-γ

Interferon-gamma

IgG

Immunoglobulin G

IL-1β

Interleukin-1β

IL-6

Interleukin-6

iNOS

Inducible nitric oxide synthase

IOM

Institute of Medicine

IVIG

Intravenous immunoglobulin

LDN

Low-dose naltrexone

MAPK

Mitogen-activated protein kinase

ME/CFS

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

MeSH

Medical Subject Headings

MMSE

Mini-Mental State Examination

MoCA

Montreal Cognitive Assessment

NAC

N-acetylcysteine

NfL

Neurofilament light chain

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NICE

National Institute for Health and Care Excellence

NK

Natural killer

NO

Nitric oxide

PACS

Post-acute COVID-19 syndrome

PBMCs

Peripheral blood mononuclear cells

PDH

Pyruvate dehydrogenase

PDKs

Pyruvate dehydrogenase kinases

PEM

Post-exertional malaise

POTS

Postural tachycardia syndrome

PSQI

Pittsburgh Sleep Quality Index

RCTs

Randomized controlled trials

RNA

Ribonucleic acid

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

RWD

Real-world data

SANRA

The Scale for the Assessment of Narrative Review Articles

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

SMN

Somatomotor network

SOD

Superoxide dismutase

TCA

Tricarboxylic acid

TCM

Traditional Chinese medicine

Th1

T-helper 1

Th2

T-helper 2

Th17

T-helper 17

TLR3

Toll-like receptor 3

TNF-α

Tumor necrosis factor-alpha

TRPM3

Transient receptor potential cation channel subfamily M member 3

tVNS

Transcutaneous vagus nerve stimulation

µOR

µ-opioid receptors

Author contributions

JF, JJ and HQC contributed equally to this work. JF, JJ, HQC, DLZ, XBL collected the literature. JF, JJ, HQC drafted the manuscript. XBL and JL constructed the figures. LMC, RJJ, XW conceived and supervised the study. All the authors have approved the final version of the manuscript.

Funding

This work was supported by the Natural Science Foundation of Sichuan Province (grant no. 2024NSFSC2123), the China Postdoctoral Science Foundation (2025M771949), the Sichuan Science and Technology Program (2025ZNSFSC1646) and the Postdoctor Research Fund of West China Hospital, Sichuan University (2025HXBH065).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.