Abstract
Background/Aim: Irisin, a myokine released during physical activity, has been proposed as a mediator of exercise’s protective effects against breast cancer (BC). This review underscores the critical role of irisin in mediating the anticancer effects of exercise and its potential application in BC prevention and prognosis.
Materials and Methods: Studies published up to 2025 were identified in PubMed, Scopus, and Web of Science databases. Data from experimental models, clinical trials, and observational studies were analyzed with emphasis on exercise-induced irisin secretion and its effects on cancer-related pathways.
Results: Irisin, derived from the precursor FNDC5 upon PGC-1α activation in skeletal muscle, regulates cancer-associated pathways by activating AMP-activated protein kinase (AMPK), inhibiting mammalian target-of-rapamycin (mTOR), modulating phosphoinositide 3-kinase (PI3K)/Akt and nuclear factor kappa B (NF-κB) signaling, and influencing transforming growth factor beta (TGF-β) activity. These actions reduce chronic inflammation, tumor proliferation, angiogenesis, and epithelial-mesenchymal transition, while enhancing apoptosis and metabolic balance. Preclinical studies demonstrate irisin’s capacity to limit BC cell viability, migration, and metastasis. Clinically, higher circulating irisin levels correlate with reduced tumor aggressiveness, fewer metastases, and better survival, though tumor may overexpress irisin as a local adaptive response. Regular moderate physical activity appears most effective in stimulating irisin secretion, although optimal exercise parameters remain to be determined.
Conclusion: Irisin exerts multifaceted anticancer effects and holds promise as a biomarker and therapeutic target in BC. Its role as a mediator of exercise benefits supports the inclusion of regular moderate physical activity in BC prevention and prognosis strategies. Further research is needed to define clinical applications and optimal exercise regimens for maximizing irisin potential.
Introduction
The awareness of the importance of physical activity in everyday functioning has been growing significantly in recent years, which can be observed across social, cultural, and scientific domains. Public health campaigns, the growing popularity of healthy living on social media, and an increasing number of scientific studies all support this trend. The beneficial role of regular physical activity is particularly evident in cardiovascular diseases, but it is also increasingly emphasized in the context of chronic diseases and cancer, including breast cancer (BC).
Malignant neoplasms represent one of the most serious global health challenges, affecting millions of people worldwide. According to the most recent GLOBOCAN 2022 estimates provided by the International Agency for Research on Cancer (IARC), approximately 20 million new cancer cases and 9.7 million cancer-related deaths were reported globally in 2022. Lung cancer was the most frequently diagnosed cancer, followed closely by BC, which accounted for 2.3 million new cases (11.5% of all diagnoses). Other common malignancies included colorectal cancer (1.9 million cases), prostate cancer (1.5 million cases), and gastric cancer (970,000 cases) (1-3).
The global cancer burden is expected to rise further in the coming decades. Projections of the World Health Organization (WHO) indicate that by 2050, the number of newly diagnosed cancer cases could reach 35 million, representing an increase of over 77% compared to levels in 2022. This sharp rise reflects complex demographic and socio-economic factors, including population aging and lifestyle changes (1).
Given the rising incidence and mortality of cancer worldwide, as well as its profound social and economic implications, effective prevention strategies are urgently needed. In this context, promoting physical activity emerges as a key and modifiable factor that may reduce the risk of developing BC and improve prognosis in affected patients.
Materials and Methods
Search strategy and eligibility criteria. We conducted a PRISMA-guided narrative review structured across four complementary domains: (i) irisin/FNDC5 and oncogenesis across tumor types; (ii) signaling pathways linking irisin to tumor-related processes (e.g., PI3K/AKT/mTOR, AMPK, EMT); (iii) exercise and cancer development, with or without concomitant irisin assessment; and (iv) irisin/FNDC5 in the context of exercise, with emphasis on breast cancer and preclinical models.
Comprehensive literature searches were performed in PubMed, Scopus, and Web of Science from database inception through 2025. A hybrid strategy combining controlled vocabulary (e.g., MeSH terms and database-specific subject headings) and free-text keywords was applied. Searches were conducted within Title/Abstract fields (PubMed), TITLE-ABS-KEY (Scopus), and Topic (TS) fields (Web of Science), as appropriate. Each thematic block was searched independently, after which records were pooled, and duplicates were removed using reference management software.
Inclusion and exclusion criteria. Eligible records included original experimental studies (in vitro/in vivo), clinical observational studies, interventional trials and review articles (systematic or narrative) that reported: (i) irisin/FNDC5 expression, secretion, or circulating levels; (ii) exercise-induced changes in irisin; (iii) associations with breast cancer and other cancer types (e.g., colorectal, ovarian, prostate, glioma) in terms of biology or outcomes.
We excluded narrative reviews without new data, editorials, case reports, non-English articles without available translations, and studies focused solely on non-oncologic endpoints without irisin-related outcomes.
Screening and study selection. Two reviewers independently screened titles/abstracts followed by full texts; discrepancies were resolved by consensus with a third reviewer. Duplicates were removed prior to screening.
The selection process is summarized in Figure 1. In brief, (N=810) records were identified across databases and additional sources. After removing (N=316) duplicates, (N=494) titles/abstracts were screened, with (N=436) full-text articles assessed for eligibility; finally, (N=214) studies were included (Figure 1).
Flow diagram summarizing the identification and selection process of studies included in this review. A total of 810 records were identified through database searches and additional sources. After removal of 316 duplicates, 494 records were screened based on title and abstract. Full-text assessment was performed for 436 articles, and 214 studies were included in the qualitative synthesis. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; N: number of records.
Data extraction and synthesis. From each included study we extracted: study design and setting; population or model; exercise modality, intensity and dose (where relevant); irisin/FNDC5 measurement method (e.g., ELISA kit vendor/catalogue number, antibody clone, sample matrix, units); and main outcomes (tumor biology endpoints, clinicopathological correlations, exercise-induced changes) with key quantitative results.
Results
Selected risk factors for breast cancer and breast cancer pathogenesis. BC is a significant health challenge that requires ongoing scientific research. The risk of BC can be increased by many factors, with the most important being age, sex, hormonal factors, and genetic predisposition (4-6).
BC might occur in patients even of 20 years of age (7). However, BC incidence in very young women is relatively low: for example, SEER data indicate that breast cancer represents only slightly more than 2% of all cancers diagnosed in women by age 20, about 20% by age 30, and over 40% by age 40 (8). Patients with a family history of BC or ovarian cancer are also at increased risk of developing BC (9).
Genetic predisposition is known to affect the occurrence of BC. It is estimated that 5-10% of breast cancer are associated with genetic factors (6). Inherited mutations within the BRCA1 and BRCA2 genes are associated with an increased risk of BC as these genes play a fundamental role in DNA repair and tumor suppression (10-13). The aforementioned genes are responsible for the homologous recombination-mediated repair of DNA double-strand breaks (13). Although mutations in the BRCA1/BRCA2 genes affect only 3-5% of BC patients, the risk of developing BC is 10-fold higher in people carrying mutations in these genes. The other genes predisposing to breast cancer include i.e. PTEN, TP53, and ATM (6, 9, 14, 15).
Individuals with a mutation in BRCA1 or BRCA2 genes are estimated to have a 56-84% lifetime risk of developing BC, highlighting the importance of genetic predisposition in disease occurrence (16). Knowledge of genetic determinants is crucial for cancer research and in the context of everyday medical practice. Early detection and intervention can significantly reduce the risk of developing BC in individuals with BRCA gene mutations, which emphasizes the importance of genetic testing in people with a family history of BC (16). The majority of breast cancer cases (>90%) are associated with sporadic somatic mutations (6). In addition to BRCA1/2, large-scale genomic studies have shown that mutations in TP53, PIK3CA, PTEN, and MAP3K1 are also frequent in BC, leading to genomic instability, dysregulated DNA repair, and activation of oncogenic signaling (13, 14). In particular, alterations in PIK3CA and PTEN result in upregulation of the PI3K/Akt axis, therefore driving tumor proliferation and survival (14, 17). Recent molecular and epigenetic analyses emphasize that not only mutations but also hypermethylation of promoters of tumor suppressor genes (e.g., BRCA1, p16) and dysregulated microRNAs contribute to BC initiation and progression. Such epigenetic signatures, together with single-nucleotide polymorphisms (SNPs) in DNA repair, may help refine personalized diagnostic and therapeutic strategies (6, 18-20).
Hormonal and reproductive factors affect BC development. Prolonged estrogen exposure plays a key role as it was demonstrated to increase the risk of BC. Reproductive factors include the age at the onset of menarche and menopause, and the late age at first childbirth. Early menstruation and late menopause, which indicate prolonged estrogen exposure, are associated with a higher risk of BC (6, 12, 21-23).
Obesity is an acknowledged risk factor for BC (24-27). Obesity results in increased levels of estrogens, which are known to promote breast carcinogenesis (28, 29). In addition, obesity-stimulated inflammation in adipose tissue is suggested to be associated with insulin resistance and an increased level of pro-inflammatory mediators such as TNFα (tumor necrosis factor α) and IL-6 (interleukin-6) (25, 26, 28, 30). Clinical evidence also highlights that in postmenopausal women, obesity and metabolic syndrome synergistically increase BC risk (27). These findings emphasize the role of metabolic health as a modifiable factor in BC prevention.
Benign breast disease (BBD) is also one of the risk factors that increases the likelihood of developing BC in women. Factors associated with a risk of BBD include hormonal factors and a family history of breast cancer (31, 32).
Normal tissues follow controlled cell growth and division, which maintain their proper structure and function. Mutations in protooncogenes and tumor suppressor genes can lead to uncontrolled proliferation of cells, resulting in cancer formation (33-35). The breast neoplastic process is initiated by cancer transformation of epithelial cells resident in milk ducts or breast lobules, followed by their excessive proliferation (12, 36). The tumor growth is supported by the tumor microenvironment (TME), including stromal cells and immune cells (e.g., tumor-associated macrophages; TAMs), which can secrete growth factors and pro-inflammatory cytokines (37). Among them, vascular endothelial growth factor (VEGF), transforming growth factor-alpha (TGF-α), IL-10, and IL-6 can be distinguished (37, 38). These molecules form a signaling network that supports tumor development by stimulating cell proliferation, angiogenesis, and immune evasion mechanisms, therefore creating a favorable microenvironment.
Exposure to cytokines, including IL-6 and TNF-α, sustains a permissive microenvironment that facilitates tumor expansion (37). Furthermore, immune evasion in metastatic breast cancer/triple-negative breast cancer could be reinforced by the expression of immune checkpoint molecules such as PD1/PD-L1, which enables cancer cells to avoid cytotoxic T-cell responses (9, 39, 40).
Pathways such as MAPK/ERK, JAK/STAT, and Wnt/β-catenin are often deregulated in breast cancer, supporting cell proliferation and invasion (14, 41, 42). Britt et al. further deeply emphasize the genetic and non-genetic risk factors for BC as well as discuss breast cancer risk models and prevention options (13). Moreover, cellular plasticity, including epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), further support metastasis and adaptation to new microenvironments (43).
In BC, five molecular subtypes are distinguished: Luminal A, normal-like, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative. These types are characterized by different receptor [estrogen receptor (ER)/progesterone receptor (PR)/HER2] and Ki-67 status (36, 44-46). Histological classification includes preinvasive and invasive breast cancer. Ductal and lobular (subtypes are found within these two groups, indicating the origin of cancer cells from breast ductal epithelium and lobular epithelium, respectively) (36, 46, 47).
All things considered, BC is a complex condition, and its risk is associated with many factors, such as genetic mutations, hormones, reproduction status, and obesity. Genetic, environmental, and lifestyle factors need to be investigated to introduce strategies that will reduce the risk of developing BC.
Effect of physical activity on BC. Physical activity plays a preventive role and improves quality of life of post-treatment breast cancer patients (13, 48, 49). The level of physical activity decreases with age, negatively impacting muscular function (50).
Reduced physical activity in cancer patients is a complex problem that affects cardiorespiratory efficiency and muscle capacity, which are essential for performing basic life activities and maintaining independence. The study showed that in the course of chemotherapy, fewer percentage of breast cancer patients experienced physical activity (51). Despite not being statistically significant, the results demonstrated that pre-diagnostic regular recreational physical activity was associated with decreased hazard ratio of mortality and disease recurrence (51).
Many studies have indicated a relationship between low physical activity and an increased risk of malignancy (52, 53). The benefits of physical exercise extend far beyond prevention, contributing to improved physical and psychological well-being in cancer survivors. For example, a meta-analysis by Fong et al. demonstrated substantial improvements in physical and psychological outcomes in cancer survivors (54). Physical activity has also been shown to reduce fatigue, improve quality of life, and promote better sleep patterns in breast cancer survivors (23, 55). Many mechanisms underlying the association between exercise and BC risk have been found. Physical activity has a significant impact on BC occurrence in women as obesity is one of the risk factors for BC. Adipose tissue secretes pro-inflammatory cytokines, such as TNF-α, IL-6, and leptin, which support cancer development. Physical activity can reduce the levels of blood estrogens, which is particularly beneficial since prolonged exposure to these hormones are associated with a higher risk of BC (56, 57). Physical activity can trigger different immune responses depending on the intensity and duration of exercise (58).
So far, studies on the effect of physical training intensity on BC prevention have been inconclusive. The study performed on rats by Siewierska et al. found that low-intensity training (LIT) resulted in lower expression of Ki-67 (acknowledged marker of proliferation) in contrast to moderate- and high-intensity training. This suggests that moderate- and high-intensity training potentially increases the proliferation of cancer cells, which might worsen the prognosis. Therefore, LIT is supposed to be beneficial because it contributed to lower division activity of cancer cells (59). A study by Westerlind et al. seems to contradict this assumption. The experiments performed on breast cancer rat model suggest that regular moderate physical activity might reduce the risk of BC in girls and young women (60). In animal models, Malicka et al. confirmed that moderate intensity training significantly reduced the number of chemically induced mammary gland tumors in rats (61). Campbell and McTiernan also summarize that moderate physical activity decreased sex hormone levels, which may decrease the risk of breast cancer (57).
Other studies suggest that moderate intensity as well as higher levels of physical activity have a protective effect, since they were associated with lower breast cancer risk (62). The study of Demarzo et al. showed that a single high-intense activity bout in non-regularly exercising rats was correlated with increased number of aberrant crypt foci (preneoplastic lesions) in colon, which may worsen the prognosis (63).
The study of Bettariga et al. suggests the supportive role of high intensity interval training (HIIT) in reducing recurrence risk (64). Their analyses revealed that HIIT increased IL-6 serum levels in breast cancer survivors (64). In addition, incubation of breast cancer cell line with post-exercise breast cancer survivor serum resulted in reduced cell growth in comparison to the control (64). However, some issues need to be taken into account: i) IL-6 derives from different sources (e.g., TME cells or skeletal muscle cells); ii) IL-6 can act stimulatory or inhibitory on cancer development; and iii) IL-6 produced by skeletal muscle is supposed to be a mediator of exercise-induced anticancer effect (65).
In conclusion, the study findings on the intensity of physical training in terms of prevention and progression of BC are inconclusive. Further research is warranted to accurately determine the mechanism and the optimal intensity and form of physical activity that will be most effective for the prevention and prognosis of BC.
Regular physical activity supports overall health and plays a key role in reducing cancer risk and improving the prognosis in BC patients. It affects many anticancer mechanisms by activating various signaling pathways. Exercise has a significant impact on signaling pathways associated with BC development, including MAPK, nuclear factor kappa B (NF-κB), TGF-β, and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways, as well as on tumor protein 53 (p53) (Table I) (28, 66-79). The NF-κB pathway plays a crucial role in the regulation of inflammatory/immunological responses and in cellular processes related to cell survival and proliferation (80, 81). The physical activity parameters may modulate the levels of NF-κB, therefore optimal physical activity programs need to be evaluated. The levels of active NF-κB were increased following intense resistance exercise (82), while moderate exercise attenuated NF-κB pathway activation (83). Another study also demonstrated the inhibitory effect of exercise on NF-κB pathway activation as well as on inflammation (84). These results suggest that suitable exercise programs have a potential to reduce chronic inflammation, leading to cancer cell proliferation suppression (mediated via NF-κB pathway inhibition) (81, 85). In addition, physical activity also affects the function of p53, a tumor suppressor protein that regulates the cell cycle and apoptosis. Regular physical activity can affect the level and activity of p53 followed by an increased DNA repair activity, which can potentially inhibit BC development (86). Upregulation of the PI3K/Akt/mammalian target-of-rapamycin (mTOR) pathway is often associated with neoplastic progression (79, 87, 88). It acts stimulatory on cell growth, proliferation, and survival as well as affects metabolism (67, 79, 89, 90). As some studies demonstrated that exercise stimulated PI3K/Akt pathway (76, 77), the anticancer role of exercise is put into question. Interestingly, the role of AMP-activated protein kinase (AMPK) and mTOR is also worth considering as AMPK was shown to be exercise-activated (91-93). AMPK is a known energy sensor that is activated under stress condition such as nutrient deficit, DNA damage, hypoxia, or ROS formation (94, 95). Active AMPK leads to stimulation of catabolic processes, including lipid oxidation, autophagy, and glucose uptake (95). Meanwhile, mTOR exists as complexes, named mTORC1 and mTORC2 (94, 96, 97). Upon the stimulation with growth factors and in the presence of nutrients, mTORC1 and mTORC2 trigger cell proliferation, growth, and survival (94, 96, 97). Of note, mTORC1 promote anabolic actions such as protein, lipid, and nucleotide synthesis (95). AMPK is one of the most known regulators of mTORC1, as AMPK activation results in mTORC1 inhibition (94, 95). As mTOR and PI3K/PTEN/AKT/mTOR is frequently upregulated in cancers, the approaches that aim to inhibit the activation of these proteins/pathway might be promising treatment options (87, 88, 98). Therefore, exercise seems to be an option that is worth considering as it was shown to activate AMPK (91-93). VEGF is considered a cancer-promoting molecule as it stimulates angiogenesis, therefore supporting tumor growth (99, 100). The role of exercise on VEGF levels is contradictory. Studies performed on BC mouse model demonstrated that exercise decreased VEGF levels in tumor specimens (101). Other analyses showed that serum VEGF concentration was decreased in athletes that completed long-term training session (102). On the other hand, exercise was positively correlated with VEGF levels in muscles (103) and acute exercise resulted in increased VEGF serum concentrations (104). The review of Ghahramani and Razavi Majd summarizes the role of exercise on angiogenesis (105).
Effects of physical activity on molecular pathways in breast cancer.
Skeletal muscles are the largest human organ, accounting for about 40% of total body weight and being an important secretory organ (116-119). They express specific proteins, such as myokines (119). Myokines are secreted during physical activity and exert anti-inflammatory and metabolic properties which could be potentially implemented in BC prevention (120). They act as mediators, taking part in the transmission of information between muscle and adipose tissue (121). In cancer, myokines (including IL-6) might counteract cancer (122, 123). IL-6 is generally linked to cancer progression (122). Meanwhile, muscle-secreted IL-6 might exert anti-inflammatory effect and inhibit cancer cell proliferation (120, 122, 124). Exercise-induced muscle-derived IL-6 that is secreted into the circulation may also be involved in WAT browning (125).
Due to reducing TGF-β levels, physical activity could play an essential role in BC prevention and cancer treatment support (72, 106, 107). TGF-β exerts different effects depending on whether it acts during normal or malignant conditions. In normal conditions or early-stage cancer, it acts as a tumor suppressor and induces apoptosis. However, it stimulates tumor progression in late cancer stages, for example, by inducing EMT in cancer cells (107, 126-128). Therefore, physical activity can change the cancer microenvironment, making it less favorable to the growth and spread of cancer cells.
Regular physical activity, which stimulates myokine secretion, may be crucial in preventing and controlling cancer development. This paper shows that irisin, which is one of the myokines, may have a potential inhibitory effect on cancer progression.
Irisin
Irisin (Ir) is a myokine released from skeletal muscle into the bloodstream in response to physical effort. It was first described by Bostrom et al. in 2012 (129). It is mainly produced by skeletal muscle (130, 131). Studies also found the presence of irisin/FNDC5 in the liver, pancreas, brain, heart, skin, adipose tissue, and kidneys; however, Ir expression was lower in comparison to its muscle expression.
Fibronectin type III domain-containing protein 5 (FNDC5) is a precursor protein of Ir. The expression of FNDC5 is increased in skeletal muscle in response to physical activity, mainly as a result of activation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathway (129). FNDC5 is a transmembrane protein and is encoded in humans by the FNDC5 gene located on chromosome 1 (1p35.1) (132, 133). The FNDC5 gene spans 8.47 kb and consists of 6 exons and 5 introns (132, 133). The FNDC5 sequence in mice and humans differs only in the start codon (ATG in mice, atypical ATA in humans) (134, 135). The analyses performed by Jedrychowski et al. demonstrated that translation of irisin in human is performed mainly through ATA start codon (136). The difference in starting codon might affect translation as the studies showed that ATA-starting human FNDC5 transcripts were hardly translated (135).
According to UniProt database, four human FNDC5 isoforms are identified that differ from each other in length (137). FNDC5 consists of a 29-amino acid signal peptide, a 94-amino acid type III fibronectin domain, a 28-amino acid potential cleavage site, a 19-amino acid transmembrane domain, and a 39-amino acid cytoplasmic domain (132, 138). FNDC5 undergoes some modifications that lead to the formation of Ir. These include proteolytic cleavage and glycosylation (139). Ir is also known to form homodimers (140). Concerning signal transduction, αV/β5 integrin complex is postulated to act as a receptor for irisin (132, 141, 142). In the context of carcinogenesis, binding of Ir to αVβ5 initiates downstream signaling cascades involved in regulation of glucose and lipid metabolism, proliferation, EMT, and metastasis (143) (Figure 2).
Schematic representation of the FNDC5 protein structure, including the signal peptide (29 amino acids), fibronectin type III domain (94 amino acids), proteolytic cleavage region (28 amino acids), transmembrane domain (19 amino acids), and cytoplasmic domain (39 amino acids). Irisin is generated by proteolytic cleavage of FNDC5, followed by N-glycosylation at Asn36 and Asn81 and subsequent dimerization. The irisin dimer acts as a ligand for αβ integrin receptors and may also bind to an unidentified membrane receptor. Adapted from Pinkowska et al. (132). FNDC5: Fibronectin type III domain-containing protein 5; aa: amino acids; Asn: asparagine; αβ integrin: alpha-beta integrin receptor.
The concentration of Ir in human plasma ranges from 3.6-4.3 ng/ml, depending on physical activity (sedentary/training) (134, 136). Interestingly, another study reported markedly different Ir concentrations in human blood, estimating average levels at 33.9±14.4 μg/ml, with a proposed normal range of 5.1-62.7 μg/ml (144). Such discrepancies likely arise from differences in the methodologies applied, most notably mass spectrometry (136) versus ELISA (144).
The reliability of Ir measurement is further complicated by potential antibody cross-reactivity with non-specific proteins (145). In particular, the use of commercial ELISA kits has been widely criticized, as many antibodies display binding to non-specific proteins. Also, it was demonstrated that some antibodies do not detect irisin, while its presence is examined samples was undoubtful (145). This might have resulted in serum concentrations that differ by several orders of magnitude across studies, underscoring that ELISA-based measurements of Ir are often unreliable without rigorous antibody validation (145, 146).
Beyond methodological discrepancies, Ir levels also appear to be shaped by physiological states and metabolic conditions. Yilmaz et al. showed that maternal body mass index (BMI) affects Ir concentrations, with overweight and obese women presenting lower breast milk but higher serum levels. Breast milk Ir was positively associated with neonatal birth weight, while serum Ir correlated with infant growth parameters. These findings expand the understanding of Ir as a systemic regulator beyond exercise, linking it to maternal metabolism and early developmental programming (147).
Adipose tissue possesses an important role in body homeostasis. White adipose tissue (WAT) has protective and insulating functions as well as stores energy in the form of lipids (148). In addition, WAT secretes adipokines such as leptin, resistin, adiponectin, IL-6, and TNF-α (149-151). Similar to white adipocytes, brown adipocytes tissue (BAT) possesses an endocrine function as well as secretes a range of batokines including FGF21, IL-6, prostaglandins, and IGF-1 (151-153). The main function of BAT is thermogenesis (151). One of the terms connected with adipose tissue is white adipose tissue (WAT) browning, which is a promising target in the fight against obesity (148). WAT browning is defined as conversion of white adipocytes into beige/brown-like/brite adipocytes (148, 151, 154, 155). Browning might be induced by many factors, including exposure to cold or exercise (151, 154). Beige adipocytes share features with white adipocytes as well as brown adipocytes (151, 154, 155). Through activating p38 MAPK/ERK signaling pathways, irisin promotes white adipocyte browning (156).
Studies of by Bostrom et al. (129) demonstrated that FNDC5 triggered the expression of Ucp1, therefore inducing browning of adipose tissue (129). The characteristic feature of brown adipocytes as well as beige adipocytes is the presence of UCP1 (151, 157). Thermogenin, an uncoupling protein (UCP1), is associated with thermogenesis and is located in the inner membrane of the mitochondria of beige/brown adipose tissue cells (130, 148, 151, 157). It is a marker of beige/brown adipose tissue and leads to proton leakage from mitochondrial intramembranous space into matrix, converting energy from metabolic substrates directly into heat (instead of ATP) (148, 151, 158). Studies showed that cold conditions attenuated the colorectal cancer growth in mice, probably through affecting brown adipose tissue (159). In addition, the similar observations were noticed in other cancer types (melanoma, breast cancer, and pancreatic ductal adenocarcinoma) (159). The increase in UCP-1 protein levels were observed under cold temperatures as well (159). Moreover, it was proposed that cold might affect cancer cell glucose and lipid metabolism (159). BAT is suggested to improve insulin sensitivity and prevent obesity by increasing energy expenditure (157).
Iglesias highlighted that Ir acts as a systemic mediator beyond adipose tissue browning as it also improves insulin sensitivity, reduces inflammation, and supports mitochondrial biogenesis (160). These pleiotropic effects not only support metabolic homeostasis but may also influence cancer development, as obesity, insulin resistance, and chronic inflammation are recognized drivers of tumor progression.
Ir also affects the AMP-activated protein kinase (AMPK) pathway, which is a key energy regulator of the cell (161, 162). The study of Lee et al. (161) demonstrated that irisin promoted glucose uptake, GLUT4 translocation into the cell membrane, and activated AMPK (161). Other experiments showed similar results; irisin increased glucose uptake in skeletal muscles of diabetic mice as well as in in vitro diabetic myocytes (162). In addition, it was proved that incubation with irisin triggered translocation of GLUT4 and fatty acid oxidation (162). The role AMPK in mediating irisin-regulated glucose uptake and fatty acid oxidation was proved by knockdown experiments (162). The contribution of AMPK in regulating irisin-induced responses was demonstrated in another study as well (163). Interestingly, irisin was shown to act antiapoptotically, anti-inflammatory, and to function as a inhibitor of oxidative stress in high glucose-treated cardiomyocytes (which represented cardiomyocyte injury) (163). In addition, this study showed that irisin expression is decreased in cardiomyocytes subjected to high glucose conditions (163), revealing the impact of some metabolites on its expression.
Jafari and Kazemi (164) investigated how high-intensity interval training (HIIT) modulates some parameters in overweight postmenopausal women (164). Analyses of irisin blood concentrations showed that its levels increased after morning as well as evening exercise (in comparison to baseline) (164). In addition, glucose and insulin levels were decreased in blood collected post-exercise (relative to baseline) (164). These results point out the importance of exercise on irisin blood concentrations and glucose metabolism.
The study by Newman et al. suggests that physical activity, both endurance and resistance exercise, induces a rapid and pronounced increase in circulating Ir, with the magnitude and duration of the response depending on exercise type and intensity. Notably, higher intensity did not always elicit a stronger effect: in endurance exercise, a higher Ir level was observed following low-intensity sessions (Low-EE) compared to high-intensity ones (High-EE) at 30 min post-exercise. The elevated Ir levels post-exercise, in relation to its pre-exercise concentrations, indicates that carefully selected training modalities may prolong the activity of this myokine, potentially relevant for health-promoting and oncological interventions (165). Based on ELISA measurements, serum mean Ir levels increased with the severity of albuminuria in T2DM patients. This ranges irisin as a candidate biomarker (166), but assay variability means its predictive/clinical utility remains unvalidated.
In an in vitro study, Grzeszczuk et al. exposed AC16 cells (cardiomyocyte model) to hypoxia (2-6 h) and found a clear upregulation of FNDC5 mRNA along with increases in irisin signal by immunofluorescence, while ELISA of culture media showed no statistically significant change across selected time points. Based on the results, Grzeszczuk et al. postulate that irisin could serve as a potential cardiovascular disease biomarker, though they emphasize the lack of the appropriate cardiomyocyte cell line for studies (167).
Irisin and BC. Ir exerts some potential anticancer properties through its anti-inflammatory effect, improvement in cell metabolism, induction of WAT browning (as obesity is one of the risk factors for breast cancer) as well as its effect on proliferation and apoptosis (122, 139, 168). It affects tumor progression through autocrine and paracrine signaling, probably by binding to integrin receptors (132, 139).
Several crucial signaling pathways relevant to cancer are modulated by Ir (Table II). During the neoplastic process, the deterioration of aerobic conditions leads to an increased levels of hypoxia-induced factor 1 alpha (HIF-1α), a response mediated inter alia by PI3K pathway (132, 169). In addition, Ir inhibits tumor cell proliferation via the AMPK-mTOR signaling pathway and inhibits cell proliferation (G1 arrest) (170). In glioma cells, Ir effectively suppresses cancer cell proliferation through elevating p21 levels and arresting cells in G2/M phase (171) (Figure 3).
Effects of irisin in cancer cell models and their implications for breast cancer.
Irisin activates AMPK, resulting in inhibition of mTOR signaling and suppression of tumor proliferation. Ir influences mediators, including STAT3, IL-6, TNF-α, NF-κB, and Snail, thereby contributing to the regulation of apoptosis and migration. Green arrows indicate activation, whereas red arrows indicate inhibition. Based on Pinkowska et al. (132). AMPK: AMP-activated protein kinase; mTOR: mechanistic target of rapamycin; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; STAT3: signal transducer and activator of transcription 3; IL-6: interleukin-6; TNF-α: tumor necrosis factor-alpha; NF-κB: nuclear factor kappa B; HIF-1α: hypoxia-inducible factor 1-alpha.
Furthermore, the myokine might reduce inflammation by modulating the NF-κB pathway or AMPK/mTOR, thereby influencing the tumor-supportive microenvironment (132, 163). Irisin may also affect TGFβ-dependent pathways. The analyses demonstrated that Ir might inhibit TGF-β signaling in the case of cardiac fibrosis (172). As TGF-β is postulated to promote tumor progression in its late stages (107), Ir is supposed to enhance tumor-suppressive activity.
Metastasis is a multi-stage process that requires cancer cells to change their adhesive and migratory properties. Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells lose adhesion and acquire the characteristics of mesenchymal cells, which increases their ability to migrate and invade (173). Ir may have a significant impact on EMT which is a key process in the cancer cell-phenotype change and progression of cancer (174). Irisin may reduce the expression of proteins characteristic of mesenchymal cells, such as N-cadherin and vimentin. These proteins are associated with increased mobility and invasiveness of cancer cells (175). Due to the above mechanisms, Ir can affect some processes of cancer development both in terms of cancer cell-phenotype change and cancer progression. It also inhibits IL-6-induced EMT by decreasing N-cadherin and vimentin expression and increasing E-cadherin expression. In addition, Ir inhibits Snail by reducing STAT3 phosphorylation, therefore limiting cancer progression (176).
As shown by the following studies, the importance of Ir in cancer is verified by examining FNDC5 presence in tumor cells, determining circulating Ir concentration, and administration of exogenous Ir. Studies performed on MCF-7 cells showed that incubation with Ir turned out to decrease cell viability. Administration of Ir and genistein to the aforementioned cells resulted in decreased colony formation ability and inhibited cancer stem cell markers expression (186). The study of Cebulski et al. revealed FNDC5 mRNA expression was elevated in BC cell lines (MCF-7, MDA-MB-231, and MDA-MB-468) compared to the control line Me16C. The expression of FNDC5 was verified in breast tumors as well. The analyses showed elevated FNDC5 levels in breast tumor samples in relation to control samples. Ir levels were also associated with some clinicopathological parameters. Interestingly, high Ir levels were associated with longer overall survival (187).
The study of Tejeda et al. highlights the correlation between Ir and obesity in postmenopausal women diagnosed with BC. It was shown that Ir levels were elevated in BC lesions of patients with obesity compared to patients with normal BMI (188). Zhang et al. showed significant relationship between serum Ir levels and the presence of spinal metastases in 148 BC patients. The patients with higher serum Ir levels did not present metastasis, which suggests a potential protective role of this hormone. In addition, a positive correlation between Ir serum concentration and the BMI was demonstrated, which may be due to many reasons (189).
Provatopoulou et al. reported decreased serum Ir levels in BC patients compared to controls. Interestingly, serum irisin concentrations positively correlated with tumor stage (190). It was showed high serum Ir concentration was correlated with high lymph node status and histological grade in BC patients, but no association was demonstrated in the case of tumor size (187).
Contrary to the results of Provatopoulou et al. (190), Panagiotou et al. demonstrated that circulating Ir levels were significantly increased in BC patients (benign as well as malignant cancer) compared to healthy individuals. Importantly, Ir concentrations correlated with some clinicopathological parameters, underscoring its potential utility as both diagnostic and prognostic biomarker (191). Studies performed in BC mice model showed that in high fat diet-treated mice, steady exercise (low- and moderate intensity) decreased the number of metastases to lungs as well as the volume of tumors in metastatic area. These observations support the hypothesis of a cancer suppressive role of irisin. The concentration of Ir in mice blood plasma also varied, its concentration was statistically higher in high-fat diet combined with moderate-intensity exercise group in comparison to a high-fat diet control group. In vitro, studies demonstrated that incubation of MDA-MB-231 cells with Ir for 10 days reduced colony forming ability. Administration of Ir to MDA-MB-231 cells resulted also in attenuated invasion as well as decreased expression of vimentin, MMP-2, MMP-9, VEGF, and HIF-1 (192).
The correlation between irisin levels in serum and tissues needs to be evaluated (132). Moreover, the determination of the role of serum irisin in cancer development is complicated due to irisin secretion by many tissues (132). In addition, the fact that its secretion is dependent on some factors, such as BMI (189), makes it more complex. Therefore, it has to be kept in mind that total serum irisin level reflects its both local and systemic expression (132). In addition, it is essential to evaluate the role of tumor-derived irisin in cancer progression. Although being challenging, distinguishing between locally expressed and systemically derived Ir is essential for accurately interpreting its dual role in BC pathophysiology.
The role of irisin in the development of other cancer types. The expression of Ir was evaluated in non-small cell lung cancer (NSCLC). Ir was detected in cancer and stromal cells of NSCLC, while Ir was not found in control lung samples. High Ir levels in stromal cells were associated with worse overall survival, the same in patients who were not treated with preoperative chemotherapy (193). Another study of Nowinska et al. also verified the impact of Ir on NSCLC progression. As the expression of FNDC5 is regulated by PGC-1α, this study aimed to correlate the levels of the aforementioned proteins in lung cancer cells and stromal cells. However, the results showed there were weak correlations between these two factors (194). In NSCLC, Ir is suggested as a molecule that regulates chemosensitivity of cancer cells to paclitaxel. The study demonstrated that Ir ameliorated chemosensitivity of NSCLC cells through inhibiting MDR1 expression (195).
The analyses of Ir levels in larynx squamous cell carcinoma showed that Ir was elevated in cancer lesions in comparison to control tissues. The levels of Ir were also correlated with clinicopathological parameters (196).The expression of Ir was increased in colorectal cancer (CRC) cells in relation to control samples. Survival analysis revealed that Ir was not associated with overall survival of CRC patients (197). In the study of Uzun et al., grade 1 and 2 colorectal adenocarcinomas lesions were characterized by increased Ir immunoreactivity compared to control samples. Surprisingly, Ir immunoreactivity was lower in grade 3 tumors in relation to grade 1 and 2 (198).
Ir levels were evaluated in gynecological cancers as well. Experiments performed on ovarian cancer cells showed that incubation with Ir attenuated cell viability, limited colony formation, and inhibited cell migration and invasion (199). In the case of epithelial ovarian cancer, the expression of irisin/FNDC5 was elevated in ovarian cancer samples than in control tissues. Here, Ir was also proposed as tumor suppressor, as it suppressed proliferation and invasion of ovarian cancer cells. The role of Ir in EMT was underscored as well (175). Ir levels were not statistically different between endometrial cancer and control samples. No correlations between Ir levels and FIGO (staging of endometrial cancer) were found (200).
Incubation of prostate cancer cell line with Ir resulted in decreased cell viability, apoptosis promotion, and decreased MMP2 and MMP9 expression (201). Administration of Ir to prostate cancer cell line PC-3 was followed by decreased viability and promoted apoptosis. Experiments showed that Ir limited tumor growth in mice model of prostate cancer (202). These results support the suppressive role of Ir on prostate cancer progression. A clinical trial was set up to evaluate the effect of exercise on blood Ir levels in prostate cancer patients as well (203).
The role of Ir in regulating chemosensitivity was also examined in pancreatic cancer. The exogenous administration of recombinant Ir to pancreatic ductal adenocarcinoma cells resulted in improved gemcitabine chemosensitivity and decreased migration (204).
He et al. provided evidence that aerobic exercise modulates circulating myokines in multiple myeloma, with Ir identified as a key mediator. In a murine model, exercise combined with standard therapy not only reduced tumor burden but also increased Ir levels, suggesting that this myokine may contribute to the anti-tumor effects of physical activity. The elevation of Ir was accompanied by enhanced NK cell activity and a reduction in regulatory T cells, highlighting its potential role in shaping an immune microenvironment unfavorable to cancer progression. The observed effects position Ir as a candidate molecule bridging exercise-induced benefits and therapeutic success, with possible applications as a prognostic marker and therapeutic target (205).
The role of Ir was verified in parotid cancer. The examination demonstrated decreased level of Ir in parotid cancer samples in relation to the controls. In addition, Ir levels in plasma and saliva were decreased in parotid cancer patients (206). In the case of head and neck squamous cell carcinoma, Ir levels were decreased in cancer lesions in comparison to control samples. The serum Ir concentrations were also lower in cancer patients than in the control ones (207). The study performed by Homa-Mlak et al. suggests that serum Ir could serve as a marker for evaluation whether radiotherapy-treated head and neck cancer patients suffer from malnutrition (208).
Taken et al. suppose that Ir could be used as a biomarker of bladder cancer. Their analyses showed that bladder cancer patients were characterized by decreased serum Ir levels in comparison to healthy volunteers. In addition, serum Ir levels may be useful for distinguishing muscle-invasive bladder cancer patients from non-muscle-invasive bladder cancer ones (209). Another study also verified the impact of Ir on bladder cancer progression. Serum Ir concentrations were demonstrated to be decreased in bladder cancer patients in relation to control volunteers. Positive correlation between serum Ir concentrations and BMI was found as well (210).
In the case of hepatocellular carcinoma patients, serum Ir concentrations were lower than in control group. In addition, serum Ir levels were decreased in stage C hepatocellular cancer patients in comparison to stage A (211).
Recent findings from animal models indicate that aerobic exercise markedly increases circulating and muscular Ir, although its downstream metabolic effects appear context dependent. ApoE−/− mice subjected to aerobic exercise presented with improved lipid profiles, accompanied by elevated Ir concentrations (serum and skeletal muscle). Interestingly, aerobic exercised - ApoE−/− mice demonstrated decreased LC3 II/LC3 I ratio, which suggests its influence on autophagy (212). Such evidence suggests that Ir may act as a compensatory regulator under pathological conditions, modulating metabolism in a manner specific to the disease.
In glioma, Ir is postulated as a tumor suppressor. Ir was demonstrated as a molecule that inhibits cell proliferation through increasing p21 levels and arresting cell cycle in phase G2/M. Ir also inhibited cancer cell invasion (171). Mao et al. demonstrated that Ir carried in small extracellular vesicles promotes bone regeneration and remodeling in an osteoporosis model. These findings suggest that a similar mechanism may also operate within the tumor microenvironment, particularly in bone metastases, where the balance between osteogenesis and adipogenesis is critical for disease progression (213). The role of Ir is also discussed in the context of non-cancer-related gastrointestinal diseases such as Inflammatory Bowel Disease and Intestinal ischemia/reperfusion (IR) injury (168, 214).
Conclusion
Recently, there has been a growing interest in research on the relationship between physical exercise, Ir expression level, and BC development. In particular, studies focus on how Ir levels change under the influence of various types of physical training and what effect the hormone has on BC development and progression. Understanding these relationships can provide valuable information about new strategies in prevention and prognosis of BC, stressing the importance of the impact of physical activity on Ir levels. Exercise may play a role in the prevention and prognosis of BC, mainly by influencing the secretion of Ir, which is produced by skeletal muscle during exercise. Ir is a factor that modulates signaling pathways associated with cancer formation and progression, including BC.
Regular physical activity affects many anticancer mechanisms, such as the reduction of chronic inflammation, regulation of the cell cycle, and modulation of metabolism through signaling pathways associated with proteins: TGF-β, NF-κB, p53, and PI3K/Akt/mTOR. Some studies have indicated that Ir could inhibit the proliferation, migration, and invasiveness of cancer cells, as well as the processes related to the EMT, which are crucial for cancer progression. As a result, regular physical activity and the increased Ir levels associated with exercise may be an essential element of prevention strategies and assessment of prognosis in BC.
Acknowledgements
The Authors wish to thank Arkadiusz Badzinski, DHSc, authorized medical interpreter and translator, for translating this paper.
Footnotes
Authors’ Contributions (CRediT)
Conceptualization, P.D. and M.W.; Writing – original draft, M.W. and P.D.; Writing – review & editing, A.P., P.D., and M.W. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received September 16, 2025.
- Revision received February 2, 2026.
- Accepted February 26, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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