Magnetic field exposure and liver disease: from current research to future directions

Abstract

As both an environmental factor and a therapeutic modality, magnetic field (MF) exposure exerts a significant regulatory effect on liver physiology and pathology. This review systematically synthesizes the current body of evidence regarding the modulatory roles of MFs in liver diseases (LDs) and elaborates on the underlying potential mechanisms. Initially, the biological basis of the interaction between MFs and hepatic tissue is delineated. Subsequently, preclinical evidence is consolidated, which demonstrates that MFs with specific parameter settings exhibit protective or therapeutic potential in experimental models of acute liver injury (ALI), metabolic dysfunction-associated steatotic liver disease (MASLD), hepatic fibrosis (HF), and hepatocellular carcinoma. Accumulating evidence indicates that MFs predominantly exert their regulatory effects by modulating interconnected biological pathways, including iron metabolism, oxidative stress, gut microbiota, as well as cellular autophagy and apoptosis. Collectively, these mechanisms constitute a complex regulatory network that underpins the hepatoprotective effects and potential therapeutic efficacy of MFs. Finally, future perspectives are proposed. While existing evidence remains predominantly preclinical, future research must prioritize the standardization of MF parameters, the further elucidation of underlying mechanisms, and the acceleration of clinical translation. These efforts are essential to definitively establish the therapeutic potential of MFs in the prevention and management of LDs.

Graphical Abstract

Introduction

The liver is an indispensable "chemical factory" in the human body, responsible for key physiological functions such as substance metabolism, detoxification, protein synthesis, and immune defense. However, this core organ is highly vulnerable to a range of diseases, constituting a significant global health burden. Viral hepatitis, particularly hepatitis B and C, remains a leading cause of cirrhosis and hepatocellular carcinoma, reportedly resulting in over one million deaths annually [1,2]. Meanwhile, with the global epidemic of obesity and type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD) has replaced viral hepatitis as the most common chronic liver disease (LD) in the world, making it a major new driver of cirrhosis and liver cancer (LC) [3,4]. According to the 2022 global cancer statistics, LC is the third leading cause of cancer-related deaths worldwide, with an extremely low five-year survival rate. This highlights the severity of liver diseases (LDs) throughout their entire course, from early metabolic abnormalities to advanced malignant tumors [5].

In the field of medicine, the use of physical modalities for disease diagnosis and treatment has a long history and forms the cornerstone of modern rehabilitation medicine and physical therapy. Among these, magnetic field (MF) therapy is garnering increasing attention due to its unique physical properties, such as deep penetration, absence of ionizing radiation, and the ability to act non-invasively on biological tissues [6,7]. An MF is a physical field generated by moving charges (electric current) or magnetic materials, capable of exerting forces on other moving charges or magnetic objects. In biomedical research, based on their time-dependent characteristics, MFs are primarily categorized into the following two types: static magnetic fields (SMFs) and dynamic magnetic fields (DMFs) [8]. An SMF refers to an MF whose strength and direction do not change over time. A DMF, on the other hand, is one whose strength or direction varies over time. In this review, electromagnetic fields (EMFs) are classified into three categories based on frequency ranges and their biological effects. According to international standards and consensus in bioelectromagnetic research: extremely low frequency EMFs (ELF-EMFs) (1 Hz to 300 Hz) [9], low frequency EMFs (LF-EMFs) (300 Hz to 30 kHz) [10], and radiofrequency EMFs (RF-EMFs) (100 kHz to 300 GHz) [11]. In this review, the term LF-MF discussed later also encompasses ELF-MF. The MFs in our daily environment primarily originate from electricity usage and the Earth itself, with intensities typically very low, mostly on the order of micro-Tesla (μT). For example, the Earth's MF ranges from 25 to 65 μT, while a mobile phone in standby or during a call mainly generates RF-EMFs, which have extremely low field strengths. The range of MF intensities in medical research is extremely broad, from μT used for measuring physiological signals to 7 T for Magnetic Resonance Imaging (MRI) [12,13].

Whether MFs are safe for the human body is a matter of public concern. Exposure of mice to a moderate SMF within the range of 0.05 T to 0.5 T showed no significant changes in lymphocytes, red blood cells, hepatocytes or platelet, etc. [14]. Even exposure to a 9.4 T quasi-uniform SMF for 14 h [15], exposure to a 2–12 T SMF for 28 days [16], or exposure to a 3.5–23.0 T SMF for 2 h did not cause obvious pathological changes in mouse tissues [17]. Conversely, Bestoon et al. reported different results: rats exposed to a 2.4 ± 0.2 mT SMF for 2 h per day over 4 weeks showed an increased density of Kupffer cells in hepatic tissue; however, exposure for 1 h or for 1 week did not produce this change [18]. Hassan et al. indicated that the occurrence of liver injury (LI) is related to MF strength [19]. As for DMFs, exposure to 1mT and 5mT ELF-EMFs for up to 40 days did not cause changes in the expression levels of apoptosis-regulating proteins or liver morphology in rat cells [20], a cross-sectional study involving 100 people also supported this result: ELF-EMF had no significant effects on demographic factors, blood parameters, and liver enzymes [21], but might affect the development of liver tissue in rat fetuses [22]. For non-fetal research, numerous scholars have reported that exposure to MFs of different frequencies and intensities, whether long or short, does not cause overt adverse reactions or abnormal development [23–25], and may even have a certain protective effect [26]. However, the alteration of metallic elements in the body induced by MFs has been confirmed by numerous scholars [14,16,27]. Furthermore, MFs may subtly influence emotions and behavior [24,28]. A few studies have also reported that MF exposure can lead to cytoplasmic vacuolization, telangiectasia, abnormal hepatocyte morphology, and edema [29], and may even cause LI [30,31]. Long-term exposure can also significantly affect survival rates [32]. However, these MFs share the common feature of ultra-high frequency, or are SMFs with a high gradient [15]. Interestingly, there are other reports on non-LF-EMF stating that no transcriptional changes were observed in mice exposed to an 85 kHz EMF or an 1800 MHz RF-EMF for multiple consecutive days, nor were there significant changes in the activities of aspartate aminotransferase (AST) and aminotransferase (ALT), or in creatinine levels [33,34].

Numerous studies have shown that MFs can influence ion channels, regulate reactive oxygen species (ROS) levels, alter cell membrane potential, and modulate multiple intracellular signal transduction pathways. As a result, they demonstrate clear therapeutic potential in areas such as inducing analgesia, reducing inflammation [35], promoting tissue repair and regeneration [36], and even inhibiting tumor growth [37]. This characteristic of MFs, which directly regulates cellular biological behaviors, offers a promising new direction for developing innovative therapies for various chronic diseases, including liver conditions.

This review aims to systematically outline the effects of different types of MFs on various LDs, summarize their underlying molecular mechanisms, and discuss the current limitations of research as well as future prospects for clinical translation. Based on existing preclinical evidence, we propose the following core hypothesis: MFs with specific parameters exert therapeutic effects on acute liver injury (ALI), steatotic liver disease (SLD), hepatic fibrosis (HF), and LC by modulating iron metabolism, oxidative stress, gut microbiota, and programmed cell death pathways including autophagy and apoptosis. In line with this hypothesis, this review focuses on answering three questions. First, whether MFs with specific parameters, including direction, intensity, frequency and exposure duration, exert beneficial or harmful effects on LDs. Second, what the core nodes are in the molecular mechanism network through which MFs intervene in LDs. Third, what the possible explanations are for the contradictory findings in existing studies, such as the directional effect of SMFs and the differences between ELF-EMFs and RF-EMFs. Ultimately, we seek to present a clear theoretical framework and to delineate experimental directions for subsequent mechanistic studies and clinical translation.

The biological basis of the interaction between MFs and the liver

The physical effects of MFs in biological systems

Living cells resemble a complex electrical system, encompassing charges, ions, currents, electric fields, and their interactions. Charged atoms (ions) with varying valences are ubiquitous in biological organisms. These include calcium (Ca²⁺), potassium (K⁺), sodium (Na⁺), and iron (Fe²⁺ and Fe³⁺). Such charged entities can flow in the form of electric currents and generate electric fields or MFs [38]. Since MFs can act on moving charges (currents), and non-uniform MFs can also affect "non-magnetic" intracellular components, it is not surprising that a wide variety of biomagnetic effects have been observed at both the cellular and systemic levels [39].

Multiple studies have reported that MFs can modulate ion channels [40,41], which play a key role in regulating cellular electrical activity and various physiological processes. Ca²⁺ ions, as versatile intracellular messengers, are responsible for mediating a wide range of cellular activities. It has been reported that MFs can regulate voltage-gated ion channels and intracellular Ca²⁺ levels [13,42]. The continuous and coordinated activity of thousands of ion channels establishes the membrane potential (voltage). Studies report that MFs can alter this membrane potential, thereby influencing cell differentiation processes and modifying their phenotypes [43,44]. Furthermore, the application of MFs can increase the membrane potential of cancer cells, subsequently reducing their invasion and migration abilities, which has been confirmed in breast cancer cell lines [45]. In contrast, for normal cells such as neuronal cells, a SMF of 0.4 T has been shown to exert protective effects and promote cell migration by improving the orientation of cytoskeletal proteins [46].

The uniqueness of the liver as a target organ

The liver possesses a remarkable regenerative capacity unparalleled by other visceral organs. Following partial resection, toxic injury, or viral infection, mature hepatocytes can rapidly exit their quiescent state and re-enter the cell cycle to proliferate, precisely restoring the liver's original mass and function. This inherent regenerative potential gives intervention measures targeting the liver a unique target, that is promoting or regulating the regenerative repair process [47].

The liver serves as the central hub for systemic metabolism in the body. Simultaneously, it is also the most crucial detoxification organ, performing biotransformation on endogenous metabolic waste, exogenous drugs, and toxins to increase their water solubility for excretion. This pivotal role implies that any external physical stimulus may profoundly impact the homeostasis of the entire organism by influencing the liver’s metabolic flux and enzyme activity [48]. Furthermore, the liver is also a vital immune organ. It receives blood from the portal vein, which is rich in gut microbial products and food antigens, and has therefore evolved a unique immune-tolerant environment. The liver harbors a large number of resident innate immune cells, such as Kupffer cells and natural killer T (NKT) cells. This distinctive cellular composition enables the liver to play a crucial role in balancing immune surveillance and immune tolerance [49].

The liver is the primary organ for iron storage and metabolic regulation in the body. It systemically controls iron homeostasis through the synthesis and secretion of hepcidin by hepatocytes and stores iron in the form of ferritin. In pathological conditions such as hereditary hemochromatosis or chronic LDs, iron overload can occur in the liver. Excessive labile iron catalyzes the production of large amounts of ROS via the Fenton reaction, leading to lipid peroxidation, DNA damage, and protein dysfunction. This exacerbates the progression of HF, cirrhosis, and even hepatocellular carcinoma, rendering the liver particularly susceptible to oxidative stress [50]. Given iron's inherent magnetic susceptibility, the impact of MFs on the liver is significantly different from that on other organs or tissues. In light of this, the present article provides an in-depth review of the most recent advancements and mechanistic insights into MF-mediated hepatic interventions.

The impact of different types of MFs on LDs

MF and ALI

LI refers to structural or functional abnormalities of the liver caused by various factors. Common etiologies include hepatotoxic drugs, viral infections, and autoimmune disorders. It is reported that 7.5 Hz and 15 Hz pulsed EMFs (PEMFs) can effectively alleviate ALI caused by sepsis, and have anti-apoptotic, anti-inflammatory and therapeutic effects [51]. Another study further reports that PEMFs reduce the levels of pro‑inflammatory cytokines IL‑1β, IL‑6, and TNF‑α, thereby preventing multiple organ failure [52]. In an endotoxin-induced rat model of ALI, LF-EMF alone had an ameliorative effect, and the combination with a 27.12 MHz RF-EMF produced even more significant effects, while modulating oxidative stress markers [53]. For drug-induced ALI, a downward-directed MF of 0.1–0.2 T can alleviate liver damage, effectively reduce liver necrosis and apoptosis, and promote cell proliferation [54]. At present, there are relatively few studies on MF therapy for LI, and further research is warranted.

MF and SLD

In recent years, multiple international societies have recommended using the overarching term SLD, which encompasses various causes of hepatic steatosis. Based on the etiology, SLD can be classified into alcohol-associated liver disease (ALD), metabolic dysfunction and alcohol-related liver disease (MetALD), and MASLD [55]. It is worth noting that authoritative experts also suggested using “metabolic dysfunction-associated fatty liver disease” (MAFLD) instead of the term “non-alcoholic fatty liver disease” [56]. Some researchers have pointed out that a downward-directed SMF with a strength of 0.1–0.2 T significantly reduced lipid accumulation in the livers of ALD mice and alleviated LI, whereas an upward-directed SMF showed either no effect or insignificant effects [57]. The results show that liver sections from T2D mice exhibited marked hepatic steatosis, continuous exposure to a downward-directed SMF reduced lipid accumulation in the livers and could lower total cholesterol levels. Interestingly, upward-directed SMF actually exacerbates large vacuolar steatosis in hepatocytes [58,59]. Further studies also support the beneficial effect of a 0.2 T downward-directed SMF on SLD, significantly reducing the body weight and liver weight in obese mice, and markedly improving dyslipidemia [60]. However, the results of Cheng et al. also indicated that an upward-directed SMF of 0.2 T has therapeutic effects when exposed for 12 h per day, whether for 3, 5, or 7 consecutive days [61]. Lv et al. have reported that SLD mice exposed daily to an upward-directed SMF with intensities ranging from 0.4 T to 0.7 T for 8 weeks showed no significant changes in liver-related indices (such as liver mass, etc.), but the treatment reduced the number of fat vacuoles and inflammatory areas in the liver, promoted the consumption of lipid droplets by activating hepatic autophagy, and thereby suppressed lipid accumulation [62].

Regarding the contradictory results mentioned above, in general, exposure to a downward-directed SMF over several weeks can improve lipid profiles and help alleviate SLD. In contrast, an upward-directed SMF provides no benefit, and may even be harmful to SLD or LI [54]. Results have shown that a horizontally oriented SMF does not benefit the treatment of diabetic mice, while an upward-directed SMF even worsens blood glucose homeostasis and glucose tolerance. Only the combination of MFs in both directions can produce therapeutic effects [63]. Given these complexities, further research is warranted to elucidate the precise mechanisms underlying these direction-dependent phenomena.

Regarding DMFs, it has been reported that PEMF exposure reduces cholesterol ester levels, significantly downregulates triacylglycerol and its metabolic intermediates, and lowers the Firmicutes-to-Bacteroidetes (F/B) ratio of the gut microbiome. In terms of regulating the expression of genes related to fat metabolism, PEMF exposure produces effects similar to exercise, enhancing the transcriptional activity of Pgc1a required for mitochondriogenesis, and upregulating the expression of Prdm16 and Cebpa, key regulators of brown adipocyte differentiation, as well as Cox7a1 and Ucp1, which are involved in mitochondrial biogenesis and respiratory activity. Combined with fecal microbiota transplantation, it significantly reduces body weight in mice with SLD [64]. As for the 1.6 mT, 15 Hz ELF-EMF, when exposed for 2 h per day for 5 weeks, it can activate the CaMKKβ/AMPK/SREBP-1c signaling pathway, thereby improving blood lipid levels and hepatic lipid metabolism [65]. Another researcher's findings are consistent with this: exposing mice to a 60 Hz EMF with a maximum field strength of 180 mT for 8 h per day over 16 weeks reduces intramyocellular lipid accumulation. This is achieved by increasing AMPK phosphorylation, which subsequently promotes the translocation and protein expression of FAT/CD-36, the protein expression of CPT-1b, and the activity of succinate dehydrogenase (SDH) and citrate synthase (CS). Ultimately, this facilitates the transport of fatty acids into the cytoplasm and induces their translocation to the sarcolemma [66]. Figure 1 summarizes the reported mechanisms of MF therapy for SLD. However, another study showed that exposure to a 1 mT ELF-EMF for 24 weeks did not affect routine blood tests or biochemical indicators, nor did it alter the morphology of the liver and kidneys. It should be noted, however, that the study did not involve the construction of an animal model for SLD [25].

Fig. 1.

Molecular mechanisms of MF therapy in ameliorating SLD. The red arrows indicate pathway activation or up-regulation, while the blue arrows represent down-regulation or inhibition (Created with BioRender.com). Exposure to MFs triggers a multi-pathway signaling cascade within hepatocytes to regulate lipid homeostasis, mainly involving two major pathways: the CaMKKβ-AMPK pathway and the MAPKs-NRF2 pathway. In particular, activation of AMPK leads to the inhibition of SREBP-1c-mediated lipogenesis, modulates FAT/CD36 membrane translocation, or influence on the activity of CS and SDH, thereby reducing exogenous free fatty acid (FFA) uptake. Concurrently, the activation of the MAPKs-NRF2-HO-1 axis enhances the cellular antioxidant defense and stimulates autophagy/lipophagy

The biological effects of RF-EMF differ from those of ELF-EMF. It has been reported that exposure of juvenile rat models to 1760 MHz RF-EMF (2 h per day for 8 weeks) leads to increased body weight, decreased insulin sensitivity, and elevated levels of triglycerides, glycogen, AST, as well as increased liver weight. This may attributable to developmental impairments of various functional components in the hypothalamic neural circuitry that receives and integrates gut-derived ascending signals, regulating intestinal tone and motility, blood glucose, hepatic glucose flux, and certain metabolic enzymes. AMPK activates the expression of the orexigenic peptide NPY in the hypothalamus and reduces the expression of the anorexigenic peptide POMC, thereby increasing food intake, which is detrimental to the management of MASLD [67]. Collectively, ELF-EMF may alleviate SLD, but further confirmation is required. In contrast, RF-EMF is more likely to exert detrimental effects.

MF and HF

HF is a pathological process characterized by the excessive deposition and abnormal distribution of extracellular matrix (particularly collagen) during the self-repair of liver tissue following chronic LI. In its early and intermediate stages, HF is considered a dynamic and potentially reversible process. However, if the injury persists, fibrosis can progressively worsen and ultimately lead to cirrhosis [68,69]. Currently, approved targeted anti-fibrotic therapies remain highly limited [69]. Emerging evidence suggests that MF interventions may offer therapeutic benefits for HF. In diabetic mice, exposure to an upward-directed SMF of 0.4–0.7 T over 8 weeks resulted in an improvement in HF. Additionally, SMF exposure reduced the expression of type I collagen, TNF-α, and MMP, while increasing the expression of α-SMA in obese mice [62]. However, it has been reported that exposure to 50 Hz EMF with intensities of 30, 100 or 500 μT for up to 24 weeks did not cause changes in fibrosis-related genes [23]. Another study reported that exposing rats to an ELF-MF with a strength of 2 mT for 30 days exacerbated HF and induced LI [70]. Research on the relationship between MFs and HF remains insufficient, and the specific effects cannot yet be definitively determined.

MF and LC

LC accounts for approximately 870,000 new cases and 760,000 deaths annually, representing a severe challenge to global public health systems [71]. Existing intervention methods still fail to meet therapeutic needs, prompting to extensive research into this disease. The effects of MFs on LC have attracted increasing interest. A cell-based study showed that exposure to a 0.5 T SMF for 72 h enhanced the inhibitory effect of capsaicin on the proliferation of HepG2 cells. This enhancement was achieved by inducing apoptosis, whereas SMF exposure alone did not produce any inhibitory effect [72].

Non-ionizing EMF at 50 Hz exhibit anti-tumor effects, inducing necrosis and apoptosis in tumor cells, and can synergistically enhance the therapeutic efficacy of doxorubicin [73]. Notably, other scholars have reported that the proliferation-promoting effect of ELF-EMF varies with the specific intensity of the EMF and different cell types; when exposed to LF-EMFs with intensities of 10 and 14 mT, cell viability increases alongside field intensity, whereas when the intensity exceeds 16 mT, the viability of some cells decreases [74]. The frequency of the EMF is also an important factor influencing its effect on cells: in the 0–100 kHz frequency range, the cell viability of normal human hepatocytes remains unaffected, but it deteriorates significantly when the frequency exceeds 150 kHz. At a frequency of 100 kHz, tumor growth is restricted and apoptosis occurs. Importantly, prolonged exposure did not cause organ damage [31].

It is reported that continuous and intermittent exposure to ELF-EMF at 50 Hz and 1 mT throughout the entire life span of experimental rats does not cause carcinogenic effects or hepatotoxicity [75]. Lerchl et al. demonstrated that continuous exposure to a 1960 MHz RF-EMF for one week did not yield any carcinogenic effects [76], and results from clinical trials indicate that multiple exposures to low-energy RF-EMFs do not cause adverse effects [77]. A systematic review shows that in tumor-prone mice, no effect of RF-EMFs on malignant tumors was observed [78]. This is consistent with reports from several other scholars, indicating that current research does not support the notion that RF-EMFs induce tumor formation [76,79]. Further studies have indicated that continuous exposure to 1.7 GHz EMFs for 72 h consistently reduces the proliferation of both cancer cells and normal cells, regardless of their tissue origin. The study suggests this is attributed to the EMF inducing cellular senescence [80]. Tables 1, 2, 3 respectively summarizes the effects of SMFs, ELF-EMFs, and medium-frequency/RF-EMFs on the liver or LDs. In summary, it is evident that MFs represent a promising therapeutic approach for LC.

Table 1.

Summary of research on the impact of SMFs on LDs

Types of liver diseases	Field direction	Field intensity	Exposure time	Results
ALI	Downward	0.1–0.2 T	48 h	Reduce LI [54]
ALD	Downward	0.1–0.2 T	12 h a day for 3 weeks	Reduce LI [57]
MASLD	Downward	0.1 T	Lasting for 12 weeks	Alleviate SLD [58]
MASLD	Upward	0.1 T	Lasting for 12 weeks	Raise blood glucose and aggravate liver steatosis [58]
MASLD	Downward	15 mT	Lasting for 10 weeks	Reduce lipid accumulation and oxidative stress [59]
MASLD	Upward	15 mT	Lasting for 10 weeks	Reduce lipid accumulation, but to a lesser extent [59]
MASLD	Downward	0.2 T	12 h a day for 10 weeks	Improve lipid metabolism [60]
MASLD	Upward	0.2 T	12 h a day for 3–7 days	Exert therapeutic effects [61]
MASLD	Upward	0.4–0.7 T	4 h daily for 8 weeks	Promote the consumption of lipid droplets and inhibit lipid accumulation [62]
MASLD	Combined (Horizontal and upward)	Horizontal 3 mT; Upward 7 kV/m	3 days and 30 days	The combination of two MFs can regulate the balance of oxidative stress [63]
HF	Upward	0.4–0.7 T	4 h daily for 8 weeks	Improve hepatic fibrosis [62]
LC	Not described	0.5 T	72 h	Enhanced inhibitory effect of capsaicin on HepG2 cells [72]

Table 2.

Summary of research on the impact of ELF-EMF on LDs

Types of liver diseases	Field frequency	Field intensity	Exposure time	Results
ALI	7.5 Hz or 15 Hz	1 mT	24 h	Reduce LI [51]
ALD	15 Hz	1.6 mT	2 h a day for 5 weeks	Reduce LI [57]
Normal liver	Not described	1mT	Lasting for 24 weeks	No obvious impact [25]
HF	50 Hz	30, 100 or 500 μT	Lasting for 24 weeks	No obvious impact [23]
LC	50 Hz	About 2.5 mT	80 min once, every other day, for a total of 5 times	Induce necrosis and apoptosis, enhance the efficacy of Doxorubicin [73]
Fetal liver	50 Hz	Not described	30 min every day, for 21 days	Fetal LI and liver degeneration [22]
Normal liver	50 Hz	0.8 mT	30 min per day, 5 days a week, for one month	Increase levels of oxidative stress [93]
LC and normal cell	60 Hz	10–14 mT	72 h	Cell viability increases with increasing field intensity [74]
LC and normal cell	60 Hz	> 16 mT	72 h	Part of the cell vitality decline [74]
MASLD	60 Hz	180 mT	8 h per day, for 16 weeks	Reduce lipid accumulation [66]
ALI	75 Hz	15 mT	1 to 5 days	Reduce inflammation and improved LI [52]

Table 3.

Summary of the effects of medium-frequency/RF-EMFs on normal liver or LDs

Field frequency	Field intensity	Exposure time	Affected diseases	Results
100 kHz	1.066 mT	0 h, 24 h, 48 h, 72 h	HCC	Inhibited the survival of HCC cells [31]
27.12 MHz	Unknown	30 min	ALI	Relieved LI [53]
900 MHz	Unknown	1 h/day, 24 days	Normal liver	Caused LI [29]
900 MHz	Unknown	24 h	Normal liver	Increased the level of oxidative stress in the liver [94]
1760 MHz	Unknown	2 h/day, 8 weeks	Normal liver	Increased metabolic dysfunction [67]
1800 MHz	Unknown	6 h / 12 h / 24 h, 20 days	Normal liver	Caused LI [30]
1800 MHz	Unknown	6 h / 12 h / 24 h, 45 days	Normal liver	Induced oxidative stress and LI [33]
2100 MHz	Unknown	30 min/day, 5 days/week, one month	Normal liver	Induced oxidative stress [93]

MFs have also demonstrated therapeutic potential in other malignancies, as evidenced by the application of ELF-EMFs in colon cancer [81], their deployment as a monotherapy or alongside chemotherapeutic agents in breast cancer [82,83], and the use of high-intensity SMFs to suppress lung cancer [84], Conversely, Maffei et al. reported that EMFs may exert carcinogenic effects promoting LC [85], mediated through alterations in cell survival, cell cycle progression, DNA integrity, and proliferation. Epidemiological studies have also suggested that EMF exposure increases the incidence of leukemia86–88 and skin cancer [89]; however, many researchers consider the evidence for carcinogenic effects to be insufficient [90–92].

Potential molecular mechanism of MF affecting LD

Oxidative stress and antioxidant defense

Oxidative stress refers to a state in which the accumulation of ROS and reactive nitrogen species (RNS) exceeds the organism’s antioxidant defense capacity, leading to cellular damage. Persistent oxidative stress serves as a common pathological basis for the onset and progression of many chronic diseases, including neurodegenerative disorders, cancer, inflammation, and autoimmune diseases [95–97]. Multiple studies have reported that oxidative stress is a key mechanism through which MFs regulate the progression of LDs.

SMF exerts antioxidant effects via modulating redox balance, thereby reducing oxidative stress systemically [54,98]. It can regulate immune cells in ALD, alleviating alcohol-induced liver inflammation and decreasing the levels of multiple cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α-1 (TNF-α1). Results from multiple experiments indicate that MFs mitigate ALD-induced ROS accumulation [57]. Regarding MASLD, MF exposure reduces hepatic mitochondrial ROS levels and enhances the activation of hepatic Nrf2, thereby boosting the antioxidant capacity of GSH/GSSG. The activities of liver glutathione reductase, thioredoxin reductase, glucose-6-phosphate dehydrogenase, superoxide dismutase (SOD), and catalase (CAT) remain unaltered [63,65]. Other scholars have further noted that SMF exposure restores the hepatic redox status by activating the MAPKs/Nrf2/HO-1 antioxidant pathway. Additionally, it upregulates the expression of mitochondrial respiratory chain genes such as COX IV, SDHA, and NDUFA9, increases SOD activity, and reduces malondialdehyde (MDA) levels in the livers of obese mice [62]. A study on ELF-EMFs suggests that such fields inhibit lipid peroxidation by activating the SIRT3-FOXO3a-SOD2 pathway [99]. Figure 2 shows the specific mechanism by which MFs affect LDs through oxidative stress.

Fig. 2.

Mechanistic overview of the dual effects of MFs on LDs. (Created with BioRender.com) Positive effects: MFs promote disease remission through both immunological and metabolic modulations. MFs regulate immune cell proportions and suppress pro-inflammatory cytokines to directly alleviate hepatic inflammation. Additionally, MFs enhance mitochondrial respiratory function (upregulating COX4, SDHA, NDUFA9) and activate two major antioxidant pathways: MAPK/NRF2 and SIRT3/FOXO3a. This cascade elevates cellular antioxidant defenses, thereby attenuating ROS accumulation and lipid peroxidation. Negative effects: Conversely, deleterious MF exposure downregulates AKT1 and NRF2 transcription, which impairs the activity of antioxidant enzymes and the expression of ICAM-1. This disruption exacerbates oxidative stress, evidenced by elevated MDA levels, ultimately accelerating the worsening of liver pathology

Nevertheless, some studies report that 10-day exposure to a high-intensity SMF (1.1 T) increases oxidative stress, blood glucose, and blood lipids in marine mollusks, although the authors did not specify the direction of the MF. Furthermore, 30-day exposure to a 1.5 mT ELF-EMF elevates lipid peroxidation in rat liver tissue [93,100], impairing hematological parameters, liver function, and renal function [101]. This finding is consistent with the study by Salameh et al., who reported that a 900 MHz EMF also elevated oxidative stress levels in fetal rats, as evidenced by increased MDA content, decreased activity of cytosolic SOD, reduced levels of mitochondrial SOD, and downregulated mRNA expression of Nrf2, protein kinase B (Akt1), ICAM‑1, and catalase [94]. Additional studies on EMF at 1800 MHz and 2100 MHz also support the above results, and all indicate that MF exposure induces LI [30,93]. The findings of Zhang et al. indicate that exposure to 30, 100, or 500 μT power‑frequency EMFs for up to 24 weeks does not induce changes in oxidative stress status, a result consistent with the research findings of the Zosangzuali team on 1800 MHz RF‑EMFs [23]. While these results may appear contradictory, differences in MF parameters and animal models warrant further comprehensive investigation.

Homeostasis of iron metabolism

Iron metabolism refers to the physiological processes of iron absorption, transport, distribution, storage, utilization, and excretion within an organism, and all are regulated through dynamic equilibrium mechanisms to sustain vital activities. Dysregulation of iron metabolism can lead to various diseases. The relationship between LD and iron metabolism is exceptionally close and complex. The liver not only serves as the primary site for iron storage but also acts as the central hub for regulating systemic iron metabolism [102]. Hepcidin is a small peptide hormone produced by the liver and serves as the primary negative regulator of systemic iron homeostasis. In most chronic LDs, signaling pathways such as inflammation suppress hepcidin synthesis, leading to uncontrolled dietary iron absorption and ultimately causing hepatic iron deposition [103].

Studies show that mice with MASLD exhibit higher serum ferritin levels, increased iron content in liver tissue, and iron deposits predominantly appearing as brown granules. After exposure to SMF, although serum ferritin levels do not change significantly, hepcidin levels increase, and the hepatic change trend is reversed. Additionally, SMF reduces the mRNA levels of FTH1 and TFRC in mouse liver [62], both of which are important factors in iron metabolism. Yu et al. found that exposure to a downward-directed SMF led to a decrease in Fe²⁺ levels in mouse pancreatic β-cells and an increase in iron efflux from pancreatic cells. However, they did not further explore whether similar changes occurred in hepatocytes [58].

Gut microbiota

With the establishment of the “gut–liver axis” theory, the bidirectional crosstalk between the gut microbiota and LDs has been increasingly elucidated in recent years. Gut dysbiosis, characterized by a decrease in beneficial commensal bacteria, overgrowth of potentially pathogenic species, and alterations in microbial metabolic activities, alters the symbiotic relationship between the microbiota and the host [104]. This results in impaired intestinal barrier integrity and increased permeability. This disruption enables microbes and their metabolites to translocate to the liver through the portal vein, activating hepatic immune cells and triggering persistent inflammation, hepatocyte injury and fibrosis, which collectively exacerbate the progression of multiple LDs [105,106]. Based on these mechanisms, interventions targeting the gut microbiota have emerged as a promising strategy for managing LDs [107]. Recent clinical trials show that fecal microbiota transplantation markedly improves outcomes in MASLD [107] and cirrhosis [108], and is well tolerated in patients with hepatic encephalopathy [109].

Mounting evidence indicates that MFs modulate the gut microbiota and thereby alter LD progression. Both 150 mT upward and downward SMFs induce profound functional shifts in the gut microbiota of adult female mice, accompanied by increased microbial abundance at the genus level. Notably, the 150 mT downward SMF exhibits a greater ability to improve metabolic function than the upward counterpart [110]. Downward-directed SMF efficiently restores the abundances of Bacteroidetes and f_Muribaculaceae in the gut microbiota of MASLD mice. Metagenomic sequencing shows that SMF modulates the abundance of genes encoding iron‑complex outer membrane receptors in the gut microbiota, potentially enhancing dietary iron uptake by the microbial community [58]. Generally, an elevated ratio of Bacteroidetes to Firmicutes is characteristic of lean, healthy individuals. Muribaculaceae is markedly depleted in high-fat diet-fed mice, and restoring the populations of Bacteroidetes and f_Muribaculaceae may improve lipid and glucose homeostasis [111,112]. One study reported that SMF exposure would reduce the proportion of thick-walled bacterial phyla in the gut microbiota of Anopheles mosquitoes. In addition, SMF reshapes the overall intestinal community structure, elevates microbial α-diversity and modulates β-diversity. RNA-seq analysis further identifies significant enrichment of genes involved in oxidative phosphorylation, linoleic acid metabolism and glycerophospholipid metabolism [60].

Programmed cell death

It is reported that the MFs are associated with multiple modes of cell death during their regulation of LD progression. SMF can increase the expression of LC3 and Atg14, induce hepatic autophagy, and thereby improve liver metabolism [62]. Some scholars have further noted that SMF induces the level of hepatic autophagy by promoting the polymerization of intracellular actin [113]. It has been reported that in the in vitro model of liver tumors, both LF-EMFs [31] and SMF [114] can induce cell apoptosis. Specifically, SMF is capable of triggering hepatocyte apoptosis through the caspase-independent apoptosis-inducing factor (AIF) pathway mediated by mitochondria [115]. As for other forms of programmed cell death such as pyroptosis and ferroptosis, no direct research has been published to date. However, relevant studies have been conducted on magnetic nanomaterials [116,117].

The aforementioned mechanisms are interrelated and constitute a complex regulatory network [118], which collectively exerts effects in MF-based therapy for LDs. Labile iron, which can interact with hydrogen peroxide may be generated in cells and tissues, catalyzing the formation of highly reactive substances and thus inducing oxidative stress [119]. Moreover, host iron homeostasis modulates the composition of the gut microbiota as well as the interactions between the host and the gut microbiota [120]. The gut microbiota can directly intervene in the production of ROS and antioxidants, and also indirectly regulate the redox balance of the intestine through multiple pathways. In turn, oxidative stress can exert reciprocal effects on the gut microbiota, triggering both local and systemic inflammation [121]. When the aforementioned balance is disrupted, such as by excessive ROS accumulation or hepatic iron overload, programmed cell death is initiated [122,123].

Critical discussion and future prospects

Although MF therapy for LDs shows promising application prospects, existing research remains at the preclinical exploratory stage, with many key scientific questions yet to be resolved. This chapter first critically synthesizes three core contradictions in the current literature and proposes testable novel hypotheses, then outlines key directions and tasks for future research, aiming to provide clear guidance for subsequent studies.

Key contradictions and unsolved issues in existing research

Inconsistency of the directional effects of SMFs

Multiple studies have shown that a downward-directed SMF (0.1–0.2 T) can significantly ameliorate ALD or MASLD [54,57], whereas an upward-directed SMF of the same intensity is not only ineffective but may even aggravate hepatic steatosis [58,59]. However, Lv et al. reported that an upward-directed SMF of 0.4–0.7 T promotes lipid droplet consumption [62]; Cheng et al. also found that short-term exposure (3–7 days) to a 0.2 T upward SMF exerts therapeutic effects [61].

This contradiction may reveal an interaction among field intensity, direction, and exposure duration. At low intensities (≤ 0.2 T), a downward-directed SMF may exert its effect by promoting iron efflux from hepatocytes [58], whereas an upward field may hinder iron efflux; at moderate intensities (0.4–0.7 T), the direction dependence diminishes, and high field intensities may override the directional effect through the activation of autophagy. Furthermore, short-term exposure may not yet reach the threshold of direction-sensitive pathways. Future studies should systematically compare combinations of field intensity and direction while simultaneously measuring liver iron content and autophagy markers to identify the optimal intervention parameters.

Opposing metabolic effects of ELF-EMF and RF-EMF

ELF-EMF (50–60 Hz) has been repeatedly reported to ameliorate SLD by activating the AMPK pathway [65]; in contrast, RF-EMF (1760 MHz) exposure in adolescent rats leads to weight gain, insulin resistance, and hepatic triglyceride accumulation, a mechanism mediated by hypothalamic regulation of NPY/POMC [67].

Frequency may be the core parameter determining metabolic effects. ELF-EMF primarily acts on peripheral tissues, enhancing fatty acid oxidation through the AMPK-PGC1α axis; conversely, RF-EMF may preferentially disrupt the hypothalamic-gut-liver neural circuit. Currently, systematic comparisons at intermediate frequencies (1–100 kHz) are lacking. It is recommended that future studies conduct frequency-gradient experiments (from 50 Hz to 1.8 GHz), measuring both peripheral and central indicators in the same model, to identify the critical frequency range that separates beneficial from harmful effects.

Divergent changes in oxidative stress markers

Most studies on SMFs/ELF-EMF report antioxidative effects, whereas some RF-EMF studies have observed pro-oxidative effects in fetal or neonatal animals. Developmental stage may be a key modulating variable: whereas the hepatic antioxidant system in the fetal/neonatal period is not yet fully mature and is more sensitive to RF-EMF, adult individuals may mount an adaptive antioxidant response through mitohormesis [22,94,124]. Future studies should replicate exposure experiments across different developmental stages, simultaneously measuring markers including Nrf2 nuclear translocation and 8-OHdG, to clarify the age-dependent risk/benefit profile.

Key directions and tasks for future research

In light of the contradictions analyzed above, several key tasks should be prioritized in future research. First, a standardized reporting framework for magnetic field parameters should be established, documenting field type, frequency, intensity, direction, exposure regimen, and animal information, as this is essential for enabling cross-study comparability.

Second, the mechanisms underlying the three major contradictions should be systematically validated. For the directional effect, markers of iron metabolism and autophagy should be examined under combinations of different field intensities and directions. For the frequency effect, frequency gradients should be established to simultaneously assess peripheral and central metabolic indicators. For the differential effects on oxidative stress response, comparisons across developmental stages are needed to elucidate age-dependent risks.

Third, mechanistic studies and combination interventions should be advanced in parallel. Germ-free mice or fecal microbiota transplantation should be used to validate whether the gut microbiota serves as a necessary mediator of MF effects. Magnetosensitive molecules should be identified via gene knockout approaches. The synergistic effects of MFs combined with low-dose chemotherapeutic agents should also be explored in LC models.

Finally, clinical translation should be accelerated. The first human trials should target MASLD, with liver fat content as the primary endpoint, and progressively move toward individualized “precision magnetic medicine”.

Conclusions

As a therapeutic modality, MFs are attracting increasing attention from researchers. Preclinical studies have demonstrated that MFs can effectively ameliorate various LDs through multiple mechanisms, including alleviating oxidative stress, regulating iron homeostasis, restoring gut microbiota homeostasis, and modulating programmed cell death (e.g., autophagy and apoptosis). Nevertheless, the specific parameters of therapeutic MFs remain to be clarified, and relevant clinical research is needed. In the future, MFs are expected to be developed into a novel adjuvant treatment for LDs, bringing benefits to patients with liver disorders.

Author contributions

JS. wrote the main manuscript text. LL. and XH. made a critical contribution and revised the first draft; Yajie Li and Yi Lv contributed to reviewing and editing the text. All authors read and approved the final manuscript.

Funding

National Natural Science Foundation of China (Grant Number: 92048202).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare that they have no conflict of interest.