CFIDS is known by several names that include Myalgic Encephalomyelitis (ME) as well as Chronic Fatigue Syndrome (CFS) [1]. Previous reports from Chernobyl and the United States have associated radiation exposure with CFIDS [2,3,4,5,6,7,8]. One report had identified chromosomal damage in a CFIDS patient cohort that had previously been screened for the presence of urinary radionuclides [9,10].

In this new systems biology model for CFIDS, the overall hypothesis is that exposure to radionuclides, either via ingestion or inhalation, leads to the constant liberation of low-level electromagnetic radiation due to radioactive decay. This could be viewed as a pathological process that develops gradually as a result of constant and repeated exposure to low doses of radiation, where localized internal damage would accumulate over time. Such an accumulation would be dependent on rates of radionuclide decay as well as the body’s ability to deal with such an exposure by depuration, damage repair, or other mechanisms [11,12].

Cell exposure to beta or gamma rays has been shown to generate UVA and blue light biophotons [13,14]. The emission of light from irradiated organic material has been documented since the 1930s [15]. More recently a group characterized the emissions using a single photon counter and showed that the emitted light is mostly in the UVA range and low wavelength blue light [16,17]. The light emission can be shown to increase with radiation dose, and the biological response varies depending on the p53 status of the cell line that is exposed to the biophotons [18]. Investigations of the mechanism revealed that photosensitizers enhanced the biological cell-killing effect of the photons while melanin suppressed it [17,19]. Further examination of the system suggested that mitochondrial function was implicated, and a study of the electron transport chain confirmed that the function of mitochondrial complex 1 was completely blocked in cells receiving photon signals from other cells exposed to ionizing radiation [20]. Taken together, this body of work proves that cells grown in media containing radioisotopes or exposed to external radiation emit biophotons. These biophotons are mainly in the UVA wavelength band, and they can trigger downstream stress-like responses in cells receiving the biophotons that were never exposed to ionizing radiation. The involvement of mitochondrial complex 1 in the mechanism strongly suggests that ATP depletion and the consequent elevation of reactive oxygen species (see below) are key components in compromising efficient cell function. The mechanism is considered to explain bystander signaling, which is a non-targeted effect where cells exposed to ionizing radiation signals in non-irradiated cells induce responses indistinguishable from those seen in directly irradiated cells [15].

The STAT1 protein is a critical cell protein for proper immune function and regulation. Without it, cells are unresponsive to interferons, thereby leaving the body defenseless against viral and bacterial infections. Previous research has shown that a subpopulation of CFIDS patients who have a STAT1 deficiency exist [41,42]. This immunodeficiency may underlie the increased susceptibility to infections seen in many patients.

In a systems model, a biphasic pattern similar to that of STAT1 activity was observed as a function of the UVA radiation dose [43]. Low-dose UVA radiation was found to directly affect STAT1 phosphorylation. Thus, low-dose UVA radiation was found to activate STAT1, while higher-dose UVA radiation suppressed STAT1. Other research groups have found UV radiation to inhibit STAT1 [44,45]. Another group developed a novel radiation-biomarker discovery platform that represented the top 500 genes identified by linear regression analysis. This platform was then reduced to a 10-hub network that included STAT1 as a significant radiation target [46]. In addition, STAT1 was found to be strongly associated with overall survival in melanoma patients, where high STAT1 mRNA levels were associated with better survival outcomes [47].

Ciguatoxins are a class of toxic polyether compounds found in fish whose consumption causes ciguatera poisoning [48]. Chronic ciguatera poisoning has been associated with CFIDS [49]. Ciguatoxins act on the neuronal voltage-dependent sodium (Na) channel NaV1.5 [50,51]. Dr. Yoshitsugi Hokama’s monoclonal antibody for CTX (Mab-CTX) directly detects alterations to NaV1.5 [52] and this specific antibody was previously identified to react with CFIDS patient blood as reported in several studies [53,54].

NaV1.5 is an integral membrane protein involved in the initiation and conduction of action potentials. Alterations to NaV1.5 have been associated with a variety of arrhythmic disorders, including long QT, Brugada, and sick sinus syndromes, as well as progressive cardiac conduction defect and atrial standstill. Changes in the NaV1.5 expression level and/or sodium current density have been frequently noticed in acquired cardiac disorders such as heart failure.

In a systems model, UVA radiation was found to hamper the fast inactivation of cardiac NaV1.5 [55]. Furthermore, the authors suggest that UVA radiation modification of NaV1.5 provides valuable clues for ischemia/reperfusion injury in the heart and the central nervous system. In addition, NaV1.5 has been found to be expressed in human melanoma cells and has been associated with cancer invasiveness and metastasis [56,57].

ASPH, or asparaginyl beta-hydroxylase, has been found to be increased in CFIDS patients [58]. ASPH is a transmembrane protein and a member of the alpha-ketoglutarate-dependent dioxygenase family [59]. In the last few decades, accumulating evidence has indicated that ASPH expression is upregulated in numerous types of human malignant cancer and is associated with poor survival and prognosis [60]. The ASPH protein aggregates on the surface of tumor cells. ASPH is highly expressed in cancers of the liver, pancreas, stomach, colon, breast, prostate, lung and brain. ASPH is necessary and sufficient to promote tumor cell migration, invasion, motility, and distant metastatic spread both in-vitro and in-vivo [61].

In a systems model, UVA radiation was found to significantly upregulate ASPH [62]. ASPH may prove to be a novel immunotherapy target for patients with melanoma [60].

NK cells, also known as natural killer cells, are a type of cytotoxic lymphocyte critical to the immune system. NK cells have the ability to recognize and kill cells in the absence of antibodies and the major histocompatibility complex, thereby allowing for a quicker immune reaction to stressed cells. NK cells and B-cell lineage differentiation derive from a common lymphomyeloid hematopoietic progenitor [63]. NK cell cytotoxicity has previously been shown to be altered in CFIDS patients, where it can impact the cell’s functionality [64]. Various NK cell subsets have been previously evaluated to uncover their degree of radiation sensitivity [65]. This group identified a highly pronounced decrease in the CD3-CD8+CD56+ bright subset of NK cells after radiation exposure. Furthermore, this subpopulation was found to be the most radiosensitive one. Interestingly, three CFIDS patient studies have each identified a decrease in CD3-CD8+CD56+ bright NK cells in these patient cohorts [66,67,68].

In a systems model, previous studies have shown that NK cell activity is suppressed by UVA radiation, which results in the suppression of delayed hypersensitivity responses and thus impacts immunity [69,70]. Furthermore, circulating CD56 bright NK cells inversely correlates with the survival of melanoma patients [71].

Changes to red blood cell rheology or shape have been previously identified in CFIDS patients [72,73,74]. Patient samples were found to lack deformability, indicated by the presence of stomatocytes or other non-discocytic surface changes on red blood cells (RBCs). RBC deformability is important for proper tissue perfusion and oxygenation due to the impact on microcirculatory blood flow.

In a systems model, previous research has shown that RBC rheology mainly depends on the spectrin network, which can be altered by oxidation processes within the cell [75]. This group used atomic force microscopy to study the changes in the spectrin matrix and RBC morphology during oxidation processes caused by UV radiation exposure. The number of normal discocytic RBCs decreased from 98% to 12% while generating increased numbers of stomatocytes, echinocytes, and spherocytes. Thus, the spectrin network was damaged by UV radiation exposure thereby adversely affecting RBC rheology and many of its downstream effects.

IFI16, also known as gamma-interferon-inducible protein 16, is a sensor for intracellular DNA and a mediator of interferon induction as well as an innate antiviral defense. It was found to be significantly upregulated in CFIDS patients [76,77]. In parallel with an increased frequency of plasmablasts in CFIDS patients with relatively short disease duration, the expression level of IFI16 was found to be negatively correlated with disease duration in this cohort. In addition, IFI16 expression showed a positive correlation with IGHV3-30–3 frequency in CFIDS patients.

In a systems model, one group demonstrated that IFI16, normally restricted to the nucleus, could be induced to appear in the cytoplasm under conditions of UV radiation-induced cell injury [78]. Furthermore, IFI16 has been shown to be a novel signature associated with overall survival and immune infiltration of skin cutaneous melanoma [79].

In a large UK Biobank CFIDS study, SLC25A15 was identified as being statistically significant. SLC25A15 encodes the Ornithine Transporter type 1 protein that transports ornithine across the inner membrane of mitochondria to the mitochondrial matrix and plays a role in the urea cycle [80]. This group suggested that SLC25A15 could be a causal gene for altered CFIDS risk.

In a systems model, one group identified that the overexpression of SLC25A15 was involved in the proliferation of cutaneous melanoma, leading to a poor prognosis [81].

ECP, also known as eosinophilic cationic protein, is a basic secretion protein involved in the immune system response [82]. ECP levels are an indicator of eosinophil-specific activation and degranulation. ECP levels have been found to be significantly higher in CFIDS patients and are modulated by exercise challenge [83,84].

In a systems model, ECP levels appear to be a novel prognostic serum marker for the overall survival outcome of melanoma patients [85]. Here, ECP levels were found to be inversely correlated with survival.

In CFIDS patients, increased temperature has been found in widely distributed regions of the brain [86]. This group reasoned that regional brain temperature has been used as a proxy for measuring neuroinflammation, with the observation that microglia activation can increase metabolic demands, potentially leading to excess heat. Interestingly, another research group had outlined the similarity in the pathophysiological mechanisms that apply to heat stroke and overlap with CFIDS [87]. According to this group, the endotoxemia pathway is increasingly considered the leading driver of severe organ damage and the main cause of death in people suffering from heat stroke.

More recently, it was reported that Transient Receptor Potential Melastatin 3 (TRPM3) activity was lost in CFIDS patients, and there was no significant difference in TRPM3 ion channel activity between CFIDS patients and post-COVID-19 patients [88]. Interestingly, TRPM3 functions as a sensor for noxious heat and underlies heat sensitivity in a subset of sensory neurons [89]. In fact, TRPM3-deficient mice exhibited clear deficits in their avoidance responses to noxious heat and in the development of inflammatory heat hyperalgesia. Heat stroke and heat dissipation, in the context of melanoma, are both involved in thermoregulation. This is in line with transient receptor potential ion channels and their role in both thermoregulation and thermosensation [90].

In a systems model, heat plays an additional role in melanoma. One group utilized thermal conductivity measurements as a tool to detect the micro-invasion of melanoma [91]. In accordance with tumor progression, effective thermal conductivity was higher in invasive melanoma. Likewise, another research group had identified fever as a factor contributing to long-term survival in a patient with metastatic melanoma [92]. They presented the unique case of a female patient who had suffered from MM for more than 13 years. The patient had several episodes of fever that were not deliberately treated with medication. After each fever episode, the patient observed the disappearance of tumors, which was confirmed by medical examination. Interestingly, since her initial diagnosis, the patient has refused most of the proposed medical treatments. Most of her malignant tumors have either disappeared or stabilized without further growth.

Exosomes are small vesicles enclosed by a lipid membrane bilayer and secreted by most cells in the body. They have been shown by a group to be released in response to the UVA bystander signal [16]. The treatment of unirradiated cells with these exosomes alone triggers a radiation-induced bystander effect, thus neatly confirming that the UVA signal triggers exosome release and may be upstream of exosomes in the mechanism of the radiation-induced bystander effect (RIBE) [93]. MicroRNAs (miRNAs) are the most numerous cargo molecules in the exosome. Because numerous miRNAs have been identified to date in CFIDS patients, researchers have chosen to focus on one in particular because of its importance to this model. One group has reported an increase in miR-21 in both moderately ill as well as severely ill CFIDS patients’ plasma and peripheral blood mononuclear cells (PBMCs) [94]. This result was confirmed in different patient cohorts. According to this group, miR-21 down-regulates the Sirt1/eNOS axis via TGF-beta and TNF-alpha pathways in endothelial cells as well as endothelial progenitor cells. However, another research group reported a significant reduction in the expression levels of miR-21 in both the NK and CD8 T-cells in CFIDS patients [95].

Among the key research findings that support a proposed systems model is that miR-21 has been identified as being intimately involved in RIBE. Significant upregulation of miR-21 was found by Xu [96] in both directly irradiated cells and bystander cells, which was confirmed by the expression of miR-21 precursor and its target genes. Additional research has generated a proposed RIBE model for exosome-mediated transfer of miR-21 [97]. Thus, in irradiated cells, the expression of miR-21 is upregulated, and as a response, miR-21 sorting to exosomes is motivated. The exosomes are secreted out from the irradiated cells, diffused into the extracellular medium, and taken up by non-irradiated cells. The miR-21 inside the exosomes is then released into bystander cells to induce bystander effects. Once the exosome cargo, including miR-21, was released into the cytoplasm of recipient or bystander cells, the increased miR-21 level regulated the relevant target gene expression and induced chromosome aberration and DNA damage. In addition, miR-21 has been found to play a key role in melanomagenesis and melanoma progression [98]. Lastly, miR-21 has been found in glomerular injury as well as glomerulosclerosis [99,100].