Researchers have studied the ability of electromagnetic fields (EMFs) to modulate gene expression in experimental studies for years, yet a satisfactory mechanistic explanation remains elusive. The authors of this publication address this knowledge gap. While searching for a precise regulatory mechanism for gene therapy applications, they identified the protein cytochrome b5 type B (Cyb5b) as a potential sensor. They also describe, for the first time, the molecular mechanism by which extremely low frequency electromagnetic fields (ELF-EMFs) directly influence gene expression and cellular regulatory processes. Though this work originates from a medical/therapeutic approach, the editor of the ElektrosmogReport believes that it has significant implications for radiation protection.
The authors performed single-cell RNA sequencing on murine brain cells exposed to ELF-EMFs (2.0 mT, 60 Hz). They identified the Lgr4 gene as the only gene whose expression is consistently and reversibly altered by EMFs, regardless of tissue type. The authors then isolated an EMF-inducible element (IE) from the promoter region of the Lgr4 gene. Using a reporter assay with a transgenic IE-coupled green fluorescent protein (GFP), they identified Cyb5b as an essential mediator. Knocking out Cyb5b completely abolished the cells’ EMF response, and reintroducing Cyb5b fully restored it. Building on this finding, the scientists examined the molecular mechanisms by which Cyb5b mediates the EMF response using live cell imaging. This revealed that a rhythmic oscillatory influx of calcium ions (Ca²⁺), mediated by the voltage-gated calcium channel Cacna1f, activate the IE. The authors subsequently validated their "gene switch" in vivo using transgenic IE-GFP and various therapeutic IE transgenes in a mouse model. Using the described ELF-EMF (2.0 mT, 60 Hz), they specifically modulated Alzheimer’s phenotypes and serotonin function in depression phenotypes in the manner of a gene therapy.
The mechanism:
The core component of the study relevant to radiation protection is the mechanistic decoding of the EMF signaling cascade. A series of robust reporter and knockout assays indicate that Cyb5b, a membrane-bound electron carrier primarily located in the mitochondrial membrane, functions as an EMF sensor. An applied ELF field induces a change in Cyb5b activity, which alters the redox status of voltage-gated calcium channels (VGCCs), particularly L-type VGCCs (Cacna1f). This modulates the opening probability of Cacna1f and triggers a characteristic pattern of rhythmic, sustained intracellular calcium oscillations. Only these calcium oscillations can generate the biological response, as opposed to calcium influx induced by pharmacological or physical means. This response consists of the activation of the transcription factor Sp7, which binds to the EMF-inducible element of the Lgr4 gene and initiates Lgr4 expression. Thus, ELF-EMF controls the formation of the Lgr4 protein.
The application in gene therapy:
To test the applicability of the IE gene switch in vivo, scientists placed various proteins under the control of the EMF-inducible element (IE) in transgenic mouse models. These proteins included OSK factors (used in regenerative medicine to reprogram cells), a pathogenic amyloid precursor protein (induces Alzheimer’s disease), and Tph2 (synthesizes serotonin and is used to treat depression-like diseases). The authors were able to induce the transgenes via EMF in a targeted manner, limited by time and to specific anatomical regions. OSK therapy partially restored aging mouse models. Similarly, locally applied EMF effectively triggered pathological Aβ42 accumulation, plaque formation, and neuroinflammation in the Alzheimer’s model. In the depression model, EMF exposure restored serotonergic activity and normalized depression-associated behavioral parameters.
Editor’s note:
This publication stands out for its excellent methodology. It employs comprehensive screening methods, repeated validation (knockout and rescue), live cell imaging, transgenic animal models, and long-term data to establish a robust evidence chain. While the authors found no evidence of harmful effects of EMF exposure in wild-type mice, the study is highly relevant from a radiation protection standpoint. For the first time, the study provides a plausible, verified molecular mechanism through which EMF can trigger specific changes in gene expression. These mediators are voltage-gated calcium channels (VGCCs), as Pall postulated in 2013 [1]. The authors interpret the observed calcium oscillations as a biological frequency code. The cell translates these specific calcium dynamics into a defined transcription program in a bioorthogonal manner. Thus, the question of whether similar signaling pathways can be activated by environmental and everyday EMF sources is more pressing than ever. It has now been demonstrated that ELF-EMFs, such as those from alternating current (50 Hz), can alter gene expression. The implications of this for other everyday EMF sources, such as wireless communication, are not yet foreseeable [2]. The authors suspect that ELF pulse modulation of the radiofrequency carrier wave plays a significant role in the biological activity of real mobile phone signals. The results show that the models underlying current exposure limits are too simplistic to make reliable predictions. For a long time, scientific publications have suggested that the biological effects of EMFs cannot be explained solely by thermal effects. Now, a key mechanism has been identified that renders the thermal dogma obsolete. However, the authors point out that more research is needed to determine the exact molecular mechanism by which EMF-induced changes in Cyb5b modulate the open state of Cacna1f. Nevertheless, the available data are robust enough to urge decision-makers to take action and reconsider existing exposure limits and the underlying models. (RH)
1. Pall ML. Electromagnetic fields act via activation of voltage‐gated calcium chanels to produce beneficial or adverse effects. Journal of Cellular and Molecular Medicine. 17(8),958–965. https://onlinelibrary.wiley.com/doi/10.1111/jcmm.12088
2. Panagopoulos DJ, Yakymenko I, De Iuliis GN, Chrousos GP. A comprehensive mechanism of biological and health effects of anthropogenic extremely low frequency and wireless communication electromagnetic fields. Frontiers in Public Health, 13, 1585441. https://www.frontiersin.org/articles/10.3389/fpubh.2025.1585441/full