Abstract
Ferroptosis is a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. MicroRNAs (miRNAs) are pivotal in modulating ferroptosis by targeting essential molecules, including SLC7A11, GPX4, ACSL4, FSP1, and several iron-handling proteins, thereby influencing cellular susceptibility to oxidative damage. Exercise-responsive miRNAs—encompassing both tissue-specific and circulating miRNAs—regulate angiogenesis, inflammation, mitochondrial biogenesis, metabolic homeostasis, and cellular stress responses. Recent research suggests that specific miRNAs, such as miR‐124, miR‐9, miR‐23, and miR‐378, are relevant to both exercise adaptation and ferroptosis. This indicates a potential molecular connection between improved muscular performance and the mitigation of excessive iron-induced oxidative stress. These overlapping miRNAs are hypothesized to enhance antioxidant defenses, regulate iron transport, and maintain mitochondrial function during repeated redox stressors, such as those encountered during strenuous physical activity. However, research gaps remain regarding tissue specificity, longitudinal alterations in miRNA expression, and the precise extent to which miRNAs promote cytoprotection against ferroptosis in exercised tissues. Future directions encompass comprehensive time-course research, interventional experiments utilizing miRNA mimics or antagomiRs, and clinical trials to substantiate the therapeutic potential of these interactions. Integrating core findings from ferroptosis research with exercise physiology may lead to innovative strategies to enhance oxidative resilience and reduce cell death across various illness scenarios.
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Introduction
Exercise is widely recognized for its benefits on cardiovascular, metabolic, and musculoskeletal health [1,2,3,4,5]. More recently, research has begun to uncover its profound molecular effects, particularly on gene regulation and programmed cell death pathways [3,4,5]. Among these, ferroptosis—a distinct, iron-dependent form of regulated cell death driven by lipid peroxidation—has emerged as a critical player in various physiological and pathological contexts, including cancer, neurodegeneration, and metabolic diseases [5, 6].
In parallel, microRNAs (miRNAs) have been identified as key post-transcriptional regulators of gene expression. These short, non-coding RNAs fine-tune cellular responses to stress, inflammation, and metabolic cues. Notably, miRNA expression is dynamically regulated by physical activity, suggesting a role in mediating the systemic adaptations to exercise [7,8,9].
Exercise is known to enhance antioxidant defenses, improve mitochondrial function, regulate iron homeostasis, and modulate lipid metabolism, all of which can influence susceptibility to ferroptosis by affecting key pathways involved in oxidative stress, lipid peroxidation, and iron handling [10, 11]. Moreover, specific exercise-responsive miRNAs have been linked to the regulation of genes central to ferroptosis, including SLC7A11, GPX4, FTH1, and ACSL4 [12,13,14,15,16]. Despite these intersections, the role of miRNAs as mediators between exercise and ferroptosis remains largely unexplored [17,18,19,20,21].
This review aims to address this gap by evaluating the potential of exercise-regulated miRNAs to modulate ferroptosis-related pathways. We hypothesize that miRNAs induced by physical activity can influence susceptibility or resistance to ferroptotic cell death in a context-dependent manner—acting not only as biomarkers but also as functional regulators of cellular fate. By integrating current evidence from exercise biology, ferroptosis research, and miRNA studies, we seek to identify key regulatory nodes and propose future directions for leveraging this axis in health and disease.
Ferroptosis: mechanisms and biological significance
Molecular mechanisms of ferroptosis
Ferroptosis stands apart from necrosis, autophagy, and apoptosis, showcasing unique characteristics in its morphology, biochemistry, and genetic composition, as revealed by an initial study [22]. Many researchers agree that cells experiencing ferroptosis typically show morphological changes similar to necrosis [23]. These characteristics encompass a compromise of cytoplasmic swelling (oncosis), mild chromatin condensation, plasma membrane integrity, and enlargement of cytoplasmic organelles. In certain instances, ferroptosis is characterised by cell separation and rounding, along with an elevation in autophagosomes [22,23,24,25,26]. Ferroptosis in one cell can purportedly propagate rapidly to neighbouring cells [27, 28]. At the ultrastructural level, cells experiencing ferroptosis often display notable changes in their mitochondria. These alterations may encompass condensation or expansion, a more compact membrane, a decrease or lack of cristae, and the rupture of the outer membrane [22, 24, 25].
Ferroptosis is defined by the buildup of iron and the oxidation of lipids (Fig. 1).
This diagram illustrates the key mechanisms driving ferroptosis, including iron accumulation, lipid peroxidation, and associated cellular changes. It also highlights regulatory antioxidant systems, external triggers, and potential therapeutic interventions targeting ferroptotic cell death
Iron can exist in two oxidation states: ferrous (Fe2 +) and ferric (Fe3 +). The iron redox cycle may influence cellular vulnerability to ferroptosis (Fig. 1). Non-heme iron in food predominantly exists as Fe3 + , which is insoluble and requires conversion to Fe2 + for absorption. In contrast to bilirubin and biliverdin, haemin and ferric ammonium citrate facilitate ferroptotic cell death induced by erastin or FINO2 [29]. In the serum, transferrin (TF) binds with Fe3⁺, and this complex is recognized by the transferrin receptor (TFRC) on the cellular membrane. Lactotransferrin (LTF) resembles transferrin (TF) in its enhancement of iron absorption and its role in the regulation of ferroptosis [30, 31]. Actin filaments, cytoskeleton components, absorb iron via TFRC. HSPB1/HSP25/HSP27 phosphorylation by protein kinase C (PKC) limits ferroptotic cancer cell death and cytoskeleton-mediated iron uptake [32].
Once TFRC takes it up, the STEAP3 metalloreductase in the endosome changes Fe3 + into Fe2 + . This mechanism facilitates the translocation of Fe2 + from the endosome to the cytosol through the solute carrier family 11 member 2 (SLC11A2/DMT1). Fe2 + inolves in transporting oxygen, generating energy, and producing iron-sulfur proteins within mitochondria. As a cofactor, iron creates redox-active (loosely-bound) and redox-inactive complexes, which increase oxidative stress and affect iron-dependent enzyme activity [33]. The depletion of NFS1 cysteine desulfurase impedes iron–sulfur cluster biosynthesis, thereby promoting erastin-induced ferroptosis [34]. In leukaemia cells, the overexpression of the ISCU reduces the severity of the ferroptosis that is induced by DHAN [35]. The results indicate that lower iron utilisation might increase sensitivity to ferroptosis [34]. By reducing mitochondrial iron absorption, the iron–sulfur cluster proteins CISD1/mitoNEET and CISD2 suppress ferroptosis [36, 37]. Fe2 + concentrations in lysosomes and the endoplasmic reticulum may cause ferroptosis, suggesting numerous intracellular iron stores are involved.
Ferritin is a protein that sequesters iron and comprises two subunits, FTL and FTH1. Both substances can be degraded in the lysosome, hence increasing the levels of free iron in the body. Inhibiting NCOA4-mediated ferritinophagy, a distinct mechanism by which cells degrade ferritin in the lysosome, results in increased iron accumulation and diminishes ferroptosis in cancer cells [38, 39]. FTMT, an iron-storage protein in mitochondria, suppresses erastin-induced ferroptosis in neuroblastoma cells [40], which exhibiting a comprehensive anti-ferroptotic role of iron-storage proteins. PCBPs function as iron chaperones, facilitating the transfer of iron to their respective protein clients. PCBP1 transports Fe2 + to ferritin, consequently inhibiting ferroptosis in hepatocytes [41]. Ultimately, the iron-efflux protein SLC40A1/ferroportin1/FPN facilitates the transport of iron into the extracellular environment, as Fe2 + is reoxidised to Fe3 + by ferroxidases such as CP or HEPH. When SLC40A1 is overexpressed, it inhibits ferroptosis induced by siramesine and lapatinib. Conversely, knocking down SLC40A1 promotes this process by affecting iron efflux in breast cancer cells [42]. PROM2 aids cellular resistance to ferroptosis by facilitating iron export through exosomes, involving the formation of ferritin-laden multivesicular bodies in breast and epithelial cancer cells [43]. Consequently, when cellular membrane iron release is controlled, ferroptosis risk increases.
Erastin and RSL3, recognised as key players in ferroptosis, interfere with the antioxidant system by boosting the buildup of iron inside cells [22]. Iron can cause the creation of too many ROS through the Fenton reaction, which then raises the risk of oxidative damage [22]. Iron also boosts ALOX or EGLN prolyl hydroxylases (PHD), which regulate lipid peroxidation and oxygen equilibrium. Systemic and local cellular iron regulation affect ferroptosis sensitivity [44]. Focussing on iron overload genes or utilising iron-chelating drugs can greatly reduce ferroptotic cell death, as detailed below. The reason why only iron produces reactive oxygen species through a Fenton reaction, not zinc, is unknown [45] It can also lead to ferroptosis [22]. An overabundance of iron may activate downstream effectors that enhance ferroptosis after lipid ROS generation.
Free radicals cause lipid peroxidation, which affects cell membrane unsaturated fatty acids. Lipid peroxidation produces LOOHs and reactive aldehydes such MDA and 4HNE, which rise during ferroptosis. Various fatty acids can be categorized as saturated, monounsaturated, or polyunsaturated. Cell membrane lipids such phosphatidylcholine, PE, and cardiolipin oxidase. ALOXs peroxidase polyunsaturated fatty acids in phospholipids, which is important for ferroptosis [46, 47]. Ferroptosis is characterized by the absence of cardiolipin peroxidation, despite the fact that mitochondria go through significant changes during this process [48].
Ferroptosis can be indicated by overproduction of genes or proteins. These include PTGS2/COX2, the primary prostaglandin production enzyme [49]. PTGS2 does not peroxidase lipids with prostaglandins during ferroptosis. ACSL4, an enzyme that processes fatty acids, is a biomarker and ferroptosis factor. The increase in ACSL4 levels leads to a notable rise in the amount of PUFA present in phospholipids. These phospholipids are prone to oxidation reactions, which can ultimately result in ferroptosis [50, 51] . Nevertheless, ACSL4 is not essential for ferroptosis in all instances, indicating that ACSL4-deficient cells can experience ferroptosis under certain conditions [52] . The activation of genes associated with antioxidant defense, such as the GSH [22] CoQ10 system [53, 54] and the nuclear factor, NRF2 transcription pathway [55]) and membrane repair, specifically the ESCRT-III pathway [56] Ferroptosis membrane damage reduction (Fig. 1). Thus, cells weigh damage and defensive responses to survive ferroptotic triggers.
One important aspect of encouraging ferroptosis is the peroxidation of PUFA at the bis-allylic position [57]. PUFA synthesis increases lipid peroxidation under oxidative stress. PUFA can have unsaturated bonds in omega-6 and omega-3 positions (LA; 18:2, GLA; 18:3, DGLA; 20:3, arachidonic acid (AA; 20:4), and AdA; 22:4). The amphiphilic properties of PUFA help keep the cell membrane fluid. Ferroptosis' main substrates for lipid peroxidation are AA and AdA (AA/AdA) [47]. PLA2 breaks down PUFAs into lysophospholipids and free PUFAs. ACSL4 and LPCAT3 are highly enriched for gene trap insertions in RSL3- or ML162-resistant KBM7 cells, a haploid CML cell line [58]. ACSL4 and LPCAT3 can produce AA/AdA derivatives that are important for ferroptosis [50, 51]. ACSL4 is essential to the first biochemical reaction that converts free AA/AdA into CoA. Creating AA/AdA-CoA derivatives and incorporating them into phospholipids requires this process. LPCAT3 then creates AA/AdA-CoA and membrane PE, resulting in AA/AdA–PE (Fig. 1). When ACSL4 or LPCAT3 is inhibited, there is a reduction in ferroptosis under different experimental conditions. Omega-6 polyunsaturated fatty acids help bring back ferroptosis sensitivity in cells lacking ACSL4, while omega-3 PUFAs do not have this effect [50]. Food supplementation with omega-3 and omega-6 PUFAs may cause ferroptosis-related IBD in rats [59]. Consequently, omega-3 and -6 polyunsaturated fatty acids may influence ferroptosis. PEX10 and PEX3-induced plasmalogen synthesis may result in fatal ferroptosis-related lipid peroxidation [60].
RNS and ROS, produced by redox reactions, regulate cell survival and death. RNS and ROS signal ferroptosis. RSL3 and Erastin inhibit the antioxidant system, explaining the antioxidant protein network that prevents ferroptotic cell death [61] (S1).
Ferroptosis is intricately linked to cellular iron metabolism and oxidative stress; thus, alterations in these processes frequently result in disease susceptibility. Mutations in oncogenes and tumour suppressors (e.g., RAS, TP53) can increase or decrease ferroptotic sensitivity in tumour cells. Immunotherapy radiation and, chemotherapy can kill cancer cells via ferroptotic pathways [62, 63]. S2 provide an overview about the implication of ferroptosis in diseases.
MicroRNAs and their role in exercise and ferroptosis
miRNAs: biogenesis and mechanisms of the action
MiRNA biogenesis begins with RNA polymerase II or III processing transcripts after transcription or concurrently [130,131,132]. About half of all miRNAs are present in protein-coding gene introns and exons. The other half exists between genes, being transcribed on their own and controlled by their own promoters [133, 134]. MiRNA clusters, often sharing similar seed regions, are viewed as a family when they are transcribed into a single long transcript [135]. The process of miRNA biogenesis is divided into two main pathways: non-canonical and canonical (see Fig. 1). MiRNAs are primarily processed via the well-established miRNA biogenesis pathway. Pri-miRNAs are produced from miRNA genes and processed by the microprocessor complex, which includes DGCR8, Drosha, and a ribonuclease III enzyme [136]. DGCR8 detects patterns on the pri-miRNA, such as N6-methyladenylated GGAC sequences, while Drosha cuts the hairpin base of the duplex, creating 2-nucleotide 3′ overhang pre-miRNAs. XPO5/RanGTP delivers pre-miRNAs to the cytoplasm, where Dicer processes them. This enzyme removes the terminal loop, forming a mature miRNA duplex [136,137,138,139] (Fig. 2).
Biogenesis and Function of Animal microRNAs with Potential Modulation by Exercise. This diagram illustrates the canonical miRNA pathway. In the nucleus, RNA polymerase II (RNAPII) transcribes primary miRNA (pri-miRNA), which is capped and polyadenylated. The Microprocessor complex, consisting of Drosha and Dgcr8, cleaves pri-miRNA into precursor miRNA (pre-miRNA), which is then exported to the cytoplasm via Exportin 5. In the cytosol, Dicer and TRBP further process pre-miRNAs into miRNA duplexes. These are loaded into the miRISC complex, which uses sequence complementarity to mediate mRNA translational repression. Physical activity may modulate several of these steps—enhancing RNAPII-driven transcription of specific miRNAs, altering Drosha/Dicer expression or activity, or influencing miRNA stability and turnover in response to oxidative stress or metabolic signals. These adaptive changes in miRNA biogenesis may contribute to the regulation of gene expression in muscle, cardiovascular, and metabolic tissues during and after exercise
The duplex's 5p and 3p strands are designated according to the 5′ or 3′ terminus of the pre-miRNA hairpin. The strands are incorporated into AGO proteins, with the guide strand—typically a 5′ uracil or a strand exhibiting reduced 5′ thermodynamic stability—being preserved. Active AGO2 cleavage or passive central mismatches diminish the passenger strand [137, 140].
Alongside the established pathway, there are various alternative miRNA biogenesis pathways that creatively use elements from the canonical pathway in distinct ways. There are different ways to categorise non-canonical pathways, including those that operate independently of Drosha/DGCR8 and those that do not rely on Dicer mechanisms [137].
In Drosha/DGCR8-independent pathways, pre-miRNAs are produced directly from spliced introns, known as mirtrons, or from 7-methylguanosine (m7G)-capped transcripts. These pre-miRNAs evade Drosha cleavage and are translocated to the cytoplasm via exportin 1. An m7G cap can create a 3' strand bias by obstructing 5' strand incorporation into AGO proteins [141, 142].
In Dicer-independent pathways, Drosha processes endogenous shRNAs into pre-miRNAs that lack sufficient length for Dicer cleavage. Instead, these pre-miRNAs are integrated into AGO2, where maturation is completed through AGO2-mediated cleavage of the 3p strand and subsequent trimming of the 5p strand [143, 144].
miRNAs have an essential function in managing gene expression in different ways, including slowing down translation, breaking down mRNA, and controlling transcription. Many studies show that miRNAs connect with particular sequences in the 3′ UTR of target mRNAs, leading to a reduction in translation, mRNA decapping, and deadenylation [145, 146]. MiRNA binding sites may be found in the 5′ UTRs of mRNA, in coding sections, and within promoters. Binding to the 5′ UTR or coding sections results in reduced gene expression, while interactions with promoter regions enhance transcription [147, 148].
Although the majority of research emphasises miRNA-mediated gene silencing, miRNAs can also induce gene expression under particular circumstances [137]. AGO2 and FXR1 activate translation by binding to 3′ UTR AREs during serum starvation or cell cycle arrest. This has been observed with miRNAs like let-7. In quiescent cells, miRNAs can augment translation through mechanisms involving FXR1 and AGO2 instead of GW182 [149, 150]. During amino acid deficiency, miRNAs bind to the 5′ UTR of ribosomal protein-encoding mRNAs to start translation [151]. miRNAs may also operate within the nucleus, where AGO2 translocates between the nucleus and cytoplasm through TNRC6A, a protein belonging to the GW182 family [152, 153]. AGO2 and miRISC engage with active chromatin at gene loci, indicating co-transcriptional and post-transcriptional functions. Nuclear miRISC can initiate mRNA degradation or directly modulate transcription through interactions with promoter regions [154, 155].
miRNAs and their role in ferroptosis
Ferroptosis, a regulated form of cell death driven by iron accumulation and lipid peroxidation, is intricately controlled by microRNAs (miRNAs). These small non-coding RNAs influence ferroptosis through multiple mechanisms, including modulation of antioxidant defenses, iron transport, lipid metabolism, and amino acid handling. This section organizes current findings based on the mechanistic pathways affected by miRNAs, and distinguishes between those that promote or inhibit ferroptosis.
Regulation of iron metabolism
Several miRNAs regulate ferroptosis through control of iron homeostasis. miR-19a suppresses IREB2 expression, reducing intracellular Fe2 + levels and consequently inhibiting ferroptosis in colorectal cancer (CRC) cells [156]. Similarly, miR-545 reduces ferroptosis in rectal cancer by targeting transferrin (TF), a protein that facilitates Fe2 + entry into cells [157]. On the other hand, miR-302a-3p enhances ferroptosis in non-small cell lung cancer (NSCLC) by targeting FPN1 (SLC40A1), promoting intracellular Fe2 + accumulation [158]. A similar effect is observed with miR-4735–3p in clear cell renal cell carcinoma, where it targets SLC40A1 to promote ferroptosis [198]. miR-124–3p inhibits Steap3, thereby lowering iron-driven lipid peroxidation and ferroptosis in hepatic ischemia/reperfusion (I/R) injury models [159].
Antioxidant systems: GPX4, SLC7A11, and FSP1 axis
GPX4 and SLC7A11 are essential components of the glutathione-dependent antioxidant system that counteracts ferroptosis. In cardiovascular contexts, blocking miR-15a-5p and miR-1224 results in upregulation of GPX4 and protects against acute myocardial infarction and hypoxia/reoxygenation injury, respectively [160, 161]. Inhibition of miR-23a-3p in cardiac fibroblasts leads to increased SLC7A11 expression and glutathione synthesis, alleviating atrial fibrillation and reducing reactive oxygen species (ROS) [162].
Conversely, several miRNAs promote ferroptosis by suppressing GPX4. These include miR-15a-3p in colorectal cancer [163], miR-1287–5p in osteosarcoma [164], and miR-324–3p in lung cancer [165]. These miRNAs bind to the 3′-UTR of GPX4 mRNA, decreasing its expression and increasing lipid peroxidation. miR-214–3p also targets ATF4 to promote ferroptosis in hepatic cancer [166], while miR-4715–3p inhibits both GPX4 and AURKA in upper gastrointestinal adenocarcinoma [167].
FSP1, functioning as a GPX4-independent antioxidant enzyme, is suppressed by miR-672–3p. Inhibition of this miRNA boosts FSP1 expression, reducing ferroptosis in spinal cord injury models [168]. Similarly, miR-4443 carried in exosomes interferes with METT3, which regulates FSP1 expression, thereby inhibiting ferroptosis in NSCLC [169].
Lipid peroxidation and enzymatic regulation
Lipid peroxidation is a hallmark of ferroptosis. miR-190a-5p reduces lipid peroxidation by suppressing GLS2, thereby mitigating myocardial infarction and ferroptosis in cardiomyocytes [170]. In glioblastoma, miR-670–3p targets ACSL4 to inhibit ferroptosis and increase resistance to temozolomide, while inhibition of miR-670–3p sensitizes cells to treatment [171]. miR-424–5p similarly reduces ferroptosis in ovarian cancer by suppressing ACSL4 [172].
The enzyme Ptgs2, associated with inflammatory lipid oxidation, is downregulated by miR-212–5p, which reduces ROS and ferroptosis in traumatic brain injury models [173].
Amino acid transport and metabolism
miRNAs also influence ferroptosis through the regulation of amino acid transporters such as SLC1A5, SLC7A11, and SLC3A2. miR-137 overexpression in melanoma suppresses SLC1A5, reducing glutamine uptake and preventing ferroptosis [174]. Likewise, miR-9 reduces glutamate metabolism by targeting GOT1, attenuating ferroptosis in melanoma cells [175].
miR-5096 and miR-375 promote ferroptosis in breast and gastric cancer cells, respectively, by targeting SLC7A11 [176]. miR-142–3p targets SLC3A2, enhancing ferroptosis in M1-type macrophages and contributing to hepatocellular carcinoma progression [177].
Transcriptional and signaling regulators
Transcription factors and stress-responsive signaling pathways also mediate ferroptosis. Bach1, a repressor of antioxidant gene expression, is targeted by miR-194 in neurovascular endothelial cells, thereby preventing ferroptosis and conferring neuroprotection [178].
TIPE, a p53-inhibitory protein, is downregulated by miR-539, promoting ferroptosis in CRC [179]. Meanwhile, miR-7-5p knockdown in cancer cells enhances ferroptosis and decreases radioresistance through iron regulation [180, 181].
HO-1, a downstream target of Nrf2, plays a protective role against oxidative stress. miR-3587 targets HMOX1 to reduce HO-1 expression and increase ferroptosis in kidney I/R injury [182].
Exercise-responsive MiRNAs
Regular exercise increases mitochondrial development and performance in skeletal muscle, enabling it adapts to exercise (Fig. 3) [183]. miRNAs significantly regulate gene expression across various cellular functions, including metabolic, replication, development, and growth processes [184,185,186,187,188,189,190,191]. At this point in time, there have been over 2200 genes found in the genomes of mammals that contain instructions for the production of microRNAs [192,193,194,195,196,197]. A group of myomiRs consists of miRNAs found in notable amounts in both heart and skeletal muscle tissues. The list includes miR-206, miR-1, miR-133a, miR-133b, miR-208b, miR-499, miR-208, and miR-486 (Fig. 4) [198,199,200,201].
Exercise-Induced miRNA Regulation of Ferroptosis
MicroRNAs involved in skeletal muscle regeneration and their connection to ferroptosis pathways. This figure illustrates the roles of key miRNAs in regulating stages of skeletal muscle regeneration, from satellite cell activation to muscle fiber formation. Notably, several miRNAs—including miR-378, miR-486, and miR-206—serve dual functions: they contribute to myogenic processes while also regulating ferroptosis via antioxidant defenses, mitochondrial protection, or lipid peroxidation. For example, miR-378 promotes muscle differentiation through Msc and has been shown to activate ferroptosis in ischemia–reperfusion injury by targeting GPX4 and SLC7A11; miR-486 enhances myofiber development and confers ferroptosis resistance by suppressing ROS accumulation. These miRNAs thus represent molecular links between muscle remodeling and ferroptotic regulation, integrating exercise-responsive signals with oxidative stress resilience
The study found that intense resistance training lowers miR-1 in skeletal muscles, which boosts protein synthesis and the IGF1/AKT signalling pathway. Resistance training boosts muscle growth by activating IGF-1/AKT and suppressing miR-1. IGF and aromatase pathways affect cancer progression, and physical activity can affect them. When activated, IGFs help cells absorb glucose from surrounding tissues for growth and development. This process may cause cancer over time. MiR-1 reduces IGF-1 mRNA in skeletal and cardiac muscle tissues, establishing a link between the two pathways. IGF and miR-1 levels are negatively correlated [202].
Research indicates that engaging in physical activity has a profound effect on skeletal muscles, emphasising its influence on the expression of miRNAs within these tissues [203]. Teenage and adult men trained together for 12 weeks in resistance. Two groups were formed based on lean body mass changes: those who responded less and those who responded more [204]. This study examined the levels of highly expressed miRNAs in the two groups to find any changes. The high-responder group had no miRNA alterations in the vastus lateralis muscle analysis of 21 miRNAs. Conversely, those who exhibited a low response had notably reduced levels of miR-378 and miR-451, along with a persistent decline in miR-26a and miR-29a within the same muscle group. The researchers found a notable link between higher levels of miR-378 and an increase in lean body mass, emphasising the value of keeping miR-378 levels in check to support lean body mass growth [204, 205]. Studies demonstrate that miR-378 affects MyoR, a protein that suppresses MyoD, which is necessary for muscle growth, to create myoblast cells. Research indicates that miR-378 impacts mitochondrial activity and energy production by changing peroxisome PGC1-β expression. Endurance activity typically raises miR-378 levels [204, 206]. A According to Ceccarelli et al., weightlifting and cycling, which incorporates anaerobic and aerobic aspects, increase miR-23a-3p (90 percent), miR-23b-3p (39 percent), miR-133b (80 percent), miR-181-5p (50 percent), and miR-378-5p (41%). We saw this spike four hours after exercise. Exercise-specific miRNAs regulate gene expression, according to a recent research [207]. Numerous studies have shown that miRNA targets are important in biological processes. These include: (1) calcium and AMP kinase regulation; (2) class IIa histone deacetylase modulation; (3) muscle function-related transcription factors like MyoD and MyoG; (4) mitochondrial factor targeting like mtTFA and FoxJ-3/MEF-2; (5) MAPK regulation; (6) Run 1, Pax3, and Sox9 regulation; and (7) growth factor expression oversight [207]. The findings indicate that miRNAs regulate muscle metabolism during exercise [207, 208].
Even brief physical activity can alter immune cell genetic pathways and inflammatory indicators, according to research. Research also shows that miRNAs affect the immunological response during exercise [209,210,211,212]. In a single session of physical exercise, Adom-Aizik et al. examined how ten 2-min cycling intervals at 76% of maximum oxygen intake affect circulating neutrophil mRNA and miRNA transcription [211]. Neutrophils make up 40–75% of mammalian white blood cells and are vital to the innate immune system. The study showed that engaging in physical activity boosts neutrophil levels in the blood and leads to important changes in gene expression [213]. The pathway study showed that the genetic component is linked to several critical inflammation pathways, including the ubiquitin-mediated proteolysis route, JAK/STAT signalling system, and Hedgehog signalling circuit [211].
Ma et al. have proven that swimming increases heart strength, called physiological cardiac hypertrophy [214]. Pik3a, Pten, and Tsc2 miRNAs (rno-miR-21, 124, 144, and 145) that manage the PI3K/AKT/mTOR signalling pathway are associated to the rise. Target miRNAs are in this pathway. Swimming and running influence left ventricular hypertrophy-related cardiac miRNAs that engage the renin–angiotensin–aldosterone pathway. Swimming raised levels of Ace-targeting miRNAs rno-miR-27a and 27b. This activity decreased rno-miR-143, which regulates cardiac Ace2 expression [215]. Swimming as an exercise therapy increased rno-miR-126 levels, which affect Spred-1 and support angiogenesis, according to Da Silva Jr et al. [216]. After 10 weeks of endurance training, rats' rno-miR-126 levels dropped dramatically. Swimming did not modify Pi3kr2 expression in rats, even though rno-miR-126 targeted it. Extended physical activity increased vastus lateralis muscle miR-1and miR-133 levels before a 12-week endurance training program [217]. MiR-206, miR-133b, miR-133a, and miR-1 decreased throughout the first twelve weeks of training. However, two weeks after the exercise program, their levels reverted to normal. After six weeks of cycling, Keller and his team found that microRNA-1 and microRNA-133 levels dropped significantly [218].
McCarthy, Esser, Drummond et al. found evidence that miRNAs may play a role in muscle adaptation throughout this process [201, 219]. Mice with functional overload and people with weight training have lower miR-1 and miR-133 levels. This increases IGF/AKT signalling and protein synthesis. A study by Davidsen and colleagues looked into how miRNA levels relate to the response to resistance training after a 12-week period [205]. Participants were categorised into two cohorts according to alterations in lean body mass following training. They were classified as "low-responders" and "high-responders". The miRNA expression levels in the vastus lateralis muscle of high-responders exhibited no significant variations. Conversely, individuals with modest reactions exhibited diminished levels of miR-378 and elevated levels of miR-451. The research indicates that a decrease in MiR-378 synthesis is significantly associated with the loss of lean body mass. They proposed that this reduction could impede muscle growth. Kirby and McCarthy observed that Gagan and associates discovered that miR-378 is crucial in inhibiting MyoR, hence facilitating muscle cell development [204, 220, 221]. Studies show that increasing miR-378 levels enhances the production of MyoD protein, aiding in muscle tissue development and reducing the suppressive effects of MyoR. This process stimulates muscle cell proliferation and satellite cell integration into muscle fibres, potentially increasing muscular growth in individuals [217].
Research has shown that rats engaging in activities like treadmill running, swimming, and voluntary exercise exhibit specific miRNAs in their hearts. These include miR-124, miR-21, miR-144, miR-17-3p, miR-133, miR-208b, miR-26-5p, miR-204-5p, miR-497-3p, miR-199a, miR-145, and miR-208a [214, 222]. An increase in the expression of microRNAs (miR-21 and miR-144) leads to a reduction in the levels of phosphatase and PTEN, which in turn controls the PI3K/AKT/mTOR signalling pathway in an indirect manner [214, 223]. Many miRNAs indirectly affect PTEN expression. TIMP3 levels are directly regulated by MiR-17-3p, which increases cardiomyocyte proliferation. Additionally, it has an indirect effect on PTEN, contributing to a growth in cardiomyocyte size [224].
Russell et al. examined untrained moderate- or high-velocity cyclists for 10 days. Their findings contrast Nielsen et al., who showed a significant rise in miR-1 and miR-29b and a decrease in miR-31 after training [217, 225]. Following an intense workout prior to training, experts discovered that certain miRNAs (miR-1, miR-133a, miR-181a, and miR-133b) showed an increase, while others (miR-23a, miR-9, miR-31, and miR-23b) exhibited a decrease. Researchers found that miR-31 is inversely associated to HDAC4 and NFR1, which can reduce muscle function gene expression [225].
Currently, extensive research has shown that miRNAs present in the bloodstream may serve as reliable indicators for particular diseases and the efficacy of medical treatments [226,227,228,229]. Numerous scientific studies have meticulously examined the influence of physical exercise on circulating miRNA levels in both healthy persons and those with medical problems. This suggests that these tiny chemicals may considerably affect the body's reaction to exercise. The miRNA composition in the bloodstream seems to vary according on the type, duration, and intensity of physical activity [230,231,232,233]. Our understanding of how circulating miRNAs evolve during CPET adaptation and AET is quite limited. Yet, engaging in physical activities that boost endurance and strength can alter miRNA profiles [234]. There has been a correlation established between an increase in physical activity and alterations in the levels of circulating ci-miRNAs [235]. Resistance training has been shown to drastically affect miRNA expression in cells. Resistance training can affect miRNA levels for 24 h after one session. MiR-206, miR-181a, miR-133a, and miR-133b change during 1 h, 4 h, and 24 h following training [236,237,238]. One session of extended physical activity notably increased the levels of miR-133a and miR-1 [239]. After a 3-h endurance training session, miR-133b, miR-181a, miR-1, and miR-133a increased, while miR-9, miR-23a, miR-31, and miR-23b decreased [234]. After a marathon, expert and rookie runners had higher blood miR-1, -133a, and -30a levels [240].
Intersecting pathways: ferroptosis, miRNAs, and exercise
While the majority of miRNAs identified thus far are linked to either ferroptosis or exercise, a select few are relevant to both contexts, suggesting potential mechanistic overlap. For example, miR‐378a‐3p is demonstrated to regulate ferroptosis by affecting SLC7A11 expression and is associated with muscle hypertrophy and mitochondrial remodelling in the context of exercise [204, 241].
A study demonstrated that decreasing mir-17-3p lowers exercise's DIC protection, affecting heart function. Malondialdehyde and Fe2 + increased in cardiac tissue whereas glutathione peroxidase 4 and Solute Carrier Family 7 Member 11 decreased, increasing ferroptosis. Dual-luciferase testing showed mir-17-3p targets KEAP1. Brusatol and SR-717 found that mir-17-3p/KEAP1 promotes ferroptosis in DIC via the CGAS/STING pathway. Reduced ferroptosis. Swimming exercise increases mir-17-3p, activates KEAP1/NRF2, and weakens CGAS/STING, promoting DIC ferroptosis [242]. This suggests an intensity- and duration-responsive effect, as aerobic training (swimming) modulates ferroptosis via miRNA regulation.
Huang et al. discovered that ferroptosis contributes to the apoptosis of neurones. Preconditioning exercises enhanced neurological function and reduced the infarct area in rats with ischaemic stroke. The preconditioning exercise reduced ferroptosis caused by stroke by lowering LPO levels, increasing GPX4 and SLC7A11, and decreasing ACSL4 expression. Research using high-throughput sequencing and dual luciferase reporter assays reveals that exercise-induced exosomal miR-484 leads to a reduction in Acsl4 levels. In addition, exosomal miR-484 produced by exercise is mostly from skeletal muscle, and inhibiting its production in skeletal muscle reduces preconditioning exercise's neuroprotective effect. In hypoxia, neuronal ferroptosis is the main programmed cell death, says this study. We found that preconditioning exercise may be an effective antioxidant intervention for cerebral ischaemia and that the ferroptosis pathway may be a therapeutic target in ischaemic stroke [243]. Inhibition of miR-23 (particularly miR-23a-3p) can increase SLC7A11 expression and protect cardiomyocytes from ferroptosis. Exercise studies show that miR-23a/b decreases after endurance sessions, potentially aiding muscle adaptation [162, 207, 208]. In a similar manner, miR-9 has the ability to inhibit ferroptosis in melanoma cells by targeting GOT1. However, it has a tendency to decrease after acute extended exercise in muscle contexts [175, 225]. MiR-124, a microRNA that suppresses ferroptosis by inhibiting Steap3, has also been documented to exhibit changes in animal models of cardiac hypertrophy induced by swimming. These modifications have created a link between PI3K/AKT/mTOR signalling and iron metabolism [159, 214].
The evidence indicating that regular exercise can influence ferroptosis via miRNA regulation offers a compelling justification for integrating physical activity into preventive and therapeutic approaches for diverse diseases [244, 245]. Table 1 also provides an overview about different miRNAs and their role in modulation of ferroptosis in exercise.
Therapeutic implications
The emerging understanding of microRNAs as a regulatory bridge between exercise and ferroptosis offers profound therapeutic implications across various disease states. This intersection provides novel avenues for intervention, ranging from non-pharmacological strategies to targeted molecular therapies.
Exercise, through its influence on exer-miRNAs, presents itself as a potent non-pharmacological modulator of ferroptosis [276]. Given that ferroptosis is implicated in the pathogenesis of numerous conditions, including neurodegenerative diseases, cardiovascular disorders, and metabolic diseases, leveraging physical activity to naturally regulate this cell death pathway holds significant promise. For instance, exercise-induced activation of the Nrf2 signaling pathway, which upregulates antioxidant defenses like GPX4 and SLC7A11, directly contributes to protection against ferroptosis-mediated cellular damage [276]. This suggests that tailored exercise regimens could serve as a primary preventive or adjunctive therapeutic strategy, harnessing the body's intrinsic regulatory mechanisms to mitigate ferroptotic injury.
Beyond direct therapeutic intervention, exer-miRNAs, particularly those transported in extracellular vesicles (EVs) like exosomes, are emerging as promising diagnostic biomarkers [277]. The dynamic expression patterns of these circulating miRNAs can reflect physiological adaptations to exercise, disease progression, and the efficacy of therapeutic interventions in ferroptosis-related conditions. For example, changes in specific exer-miRNAs in blood or other physiological fluids could provide non-invasive indicators of cellular stress, redox balance, or the extent of ferroptotic activity in various tissues [278]. This diagnostic potential could lead to more personalized and timely clinical management, allowing for early detection and monitoring of disease states influenced by ferroptosis.
Furthermore, exer-miRNAs represent novel and attractive therapeutic targets for precision medicine [266]. The ability of specific miRNAs to either inhibit or induce ferroptosis by modulating key genes involved in iron metabolism, lipid peroxidation, or antioxidant defense opens up opportunities for developing miRNA-based therapies. This could involve the delivery of synthetic miRNA mimics to restore beneficial miRNA levels (e.g., miR-1, miR-486-5p, miR-29a-3p) or the use of anti-miRNA oligonucleotides to inhibit detrimental miRNAs (e.g., miR-208a/b, miR-214-3p) [266]. The use of exosome-based delivery systems is particularly appealing, as exosomes naturally transport miRNAs and can be engineered for targeted delivery to specific cell types or tissues, potentially bypassing some of the challenges associated with conventional drug delivery [264]. Such targeted miRNA interventions could potentially mimic or enhance the protective effects of exercise, offering a molecular strategy to control ferroptosis in clinical settings, especially for patients unable to engage in physical activity. This approach could also be combined with existing therapies to improve patient outcomes, for example, by sensitizing cancer cells to ferroptosis-inducing chemotherapies (280).
Knowledge gap and future direction
Despite the growing evidence linking exercise‐responsive miRNAs to ferroptosis regulation, several research gaps remain that warrant deeper exploration:
Tissue‐specific profiling and mechanisms
Most available data derive from skeletal muscle or cardiac tissue, while ferroptosis studies often focus on cancer cells or neurons. Direct investigations into whether exercise‐induced miRNA fluctuations in skeletal and cardiac muscle also occur in liver, kidney, or brain tissues are scarce. Determining if these changes are tissue‐specific or systemic will be crucial for clarifying how exercise influences ferroptosis in various organs. Additionally, understanding the mechanistic underpinnings—whether the same miRNA exerts similar or distinct effects on iron handling and oxidative stress in different cell types—remains a major unanswered question.
Longitudinal time‐course studies
Although acute exercise bouts elicit rapid miRNA responses, our knowledge of how these miRNAs change over prolonged training cycles is limited. Future research should use standardized protocols to map the dynamic expression of miRNAs (e.g., miR‐378, miR‐23, miR‐9, and miR‐124) during different phases of training (e.g., early, middle, and late). Longitudinal tracking could shed light on how short‐term surges in reactive oxygen species (ROS) integrate with chronic adaptations in redox homeostasis and whether these adaptations diminish or enhance ferroptotic susceptibility over time.
Interventional studies with AntagomiRs or mimics
Proof‐of‐concept experiments using miRNA overexpression or knockdown in vivo would help confirm causality. For instance, specifically inhibiting miR‐23a‐3p or miR‐378 in an exercised animal model could clarify the extent to which these miRNAs mitigate or exacerbate ferroptosis during high oxidative stress. Conversely, boosting their expression might reveal whether they protect muscle cells from iron‐driven lipid peroxidation under conditions of intensive training or in disease states characterized by excessive oxidative damage.
Role of exercise mode, intensity, and duration
Current evidence often lumps together multiple exercise modalities, with few studies dissecting differences between resistance versus endurance training or low‐ versus high‐intensity protocols. Detailed comparisons are needed to understand how each exercise parameter modifies miRNA expression profiles and ferroptosis outcomes. Such data could inform personalized training regimens aiming to optimize both performance and cytoprotection against iron‐dependent oxidative injury. Although existing data suggest that exercise modulates key ferroptosis-related miRNAs such as miR-17-3p, miR-484, and miR-23a-3p, a detailed understanding of how training variables influence this regulation remains unexplored. This represents a promising area for future translational research in both disease prevention and exercise-based therapy.
Clinical relevance and translational potential
While animal and in vitro findings are informative, clinical translation remains limited. It is unclear whether modulating ferroptosis‐related miRNAs through exercise (or miRNA‐based interventions) could effectively prevent or treat human diseases such as cardiac ischemia‐reperfusion injury, neurodegenerative disorders, or cancer. Long‐term intervention trials, possibly monitoring circulating miRNAs alongside established ferroptosis biomarkers (e.g., lipid peroxidation products, ferritin, and transferrin saturation), would advance our understanding of clinical utility.
Interaction with other cell death pathways
Ferroptosis often coexists with apoptotic and autophagic pathways, especially during intense or prolonged stress. Distinguishing the contribution of ferroptosis from these other modes of cell death under exercise conditions is critical to unveil whether exercise preferentially modulates ferroptosis or acts more broadly on oxidative‐stress responses. Multifactorial analyses could disentangle the respective influence of individual miRNAs on ferroptosis versus apoptosis or necroptosis, leading to a more complete mapping of exercise‐induced cytoprotection.
Personalized medicine approaches
Inter‐individual variability in exercise responsiveness is well known in muscle growth and performance enhancement; similarly, the extent of ferroptosis inhibition may differ among individuals. Future work should address how baseline miRNA levels, genetic backgrounds, and comorbidities shape a person’s ferroptotic vulnerability and exercise‐induced miRNA regulation. Such insights might pave the way for personalized exercise prescriptions or targeted miRNA therapies that maximize health benefits while minimizing cellular damage.
Addressing these gaps will require interdisciplinary collaborations that integrate exercise physiology, molecular biology, and clinical trial design. By clarifying how ferroptosis intersects with the cellular adaptations inherent to exercise, investigators can more precisely target oxidative‐iron‐dependent cell death pathways, ultimately improving therapeutic strategies for a range of diseases where ferroptosis plays a central role.
Conclusion
Growing evidence supports a convergence of ferroptosis regulation and exercise physiology through shared miRNA‐mediated pathways. By influencing key ferroptosis regulators such as GPX4 and SLC7A11, while also modulating anabolic and metabolic programs essential for muscle adaptation, miRNAs provide a potential mechanistic nexus that confers resilience against iron‐catalyzed oxidative injury in active tissues. Understanding how these miRNAs fluctuate across different exercise modalities, intensities, and durations will be pivotal in mapping their precise roles in safeguarding cells from ferroptosis. Equally important is determining whether personalized exercise regimens or targeted miRNA interventions can optimize both athletic performance and protection against oxidative stress. Continued exploration of these questions in diverse tissues and patient populations, supplemented by direct in vivo manipulation of ferroptosis‐related miRNAs, will offer the clearest path toward novel translational strategies. Ultimately, the integration of ferroptosis research and exercise science has the potential to illuminate new avenues for preventing and treating conditions that involve dysregulated iron metabolism and oxidative damage, further underscoring the therapeutic promise of harnessing miRNA biology.
Data Availability
No datasets were generated or analysed during the current study.
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Anhui Provincial Philosophy and Social Science Planning Project "Decision-making analysis and research on the effect of college sports in the national delayed retirement strategy" (AHSKY2022D190).
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Lin, Z., Feng, Z. MicroRNAs at the crossroads of exercise and ferroptosis: a regulatory bridge. Clin Exp Med 25, 234 (2025). https://doi.org/10.1007/s10238-025-01766-0
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DOI: https://doi.org/10.1007/s10238-025-01766-0