Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy. In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1–dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP). While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation. We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases. Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets.
Rusin et al. (Wed,) studied this question.