Irisin: The Hormone of Exercise Rewriting the Rules of Human Physiology

Abstract

Irisin, a novel myokine produced by skeletal muscle, has garnered significant attention in recent years due to its potential therapeutic implications. This review aims to provide a comprehensive overview of the current literature on irisin, highlighting its physiological functions, molecular mechanisms, and clinical relevance. We discuss the role of irisin in regulating energy metabolism, insulin sensitivity, and inflammation, as well as its potential therapeutic applications in metabolic disorders, cardiovascular disease, and cancer. Furthermore, we examine the current methods for measuring irisin levels and the factors influencing its circulating concentrations. Finally, we identify gaps in the current knowledge and propose future research directions to further elucidate the therapeutic potential of irisin. This review provides a critical analysis of the existing literature, highlighting the promise of irisin as a novel therapeutic target for various diseases.

Keywords

Introduction

4. Effects of Exercise on Irisin:

Myokines produced by muscles during contraction are thought to be released in response to physical activity, potentially bridging the connection between regular exercise and reduced risk of chronic diseases, as well as the association between inactivity and these health conditions. Steward et al. (2012) published an early study on humans, which investigated the relationship between the expression of FNDC5 and PGC-1α genes and aerobic performance, as measured by maximal oxygen uptake (VO2max) and gas exchange (VE/Vco2), in 24 adult men suffering from heart failure and exercise intolerance due to symptoms and musculoskeletal disorders associated with the disease. Research has found a statistically significant correlation between PGC-1α and FNDC5 genes and aerobic capacity, which aligns with the findings in a study by Bostrom et al. [1]. Skeletal muscle cells secrete a polypeptide hormone called irisin. Fibronectin Type III Domain-Containing 5 (FNDC5) is the gene that produces it. Exercise causes the release of PGC-1, which is induced by the gamma coactivator 1-alpha (PGC-1α) peroxisome proliferator-activated receptor. According to research on mice, PGC1α raises FNDC5 expression, which causes irisin to be released in muscle tissue when exercise is performed. Irisin is released after FNDC5 is synthesized as a result of intracellular ATP depletion. Perakakis et al. (2017) suggested that the duration of exercise is critical for detecting higher irisin levels after analysing the physiology and irisin's role in glucose homeostasis. Training usually causes healthy adults and older people to have increased amounts of irisin. However, the rise is more noticeable in young adults who are overweight, obese, or have type 2 diabetes, necessitating longer and more severe aerobic, resistance, or mixed exercise. Although some research suggests that sex influences irisin level variations, the effects of different training techniques on circulating irisin levels generally do not differ by sex. It deserves more research [6].

 1.Stimuli triggering irisin production: Exercise, cold exposure, and non-shivering thermogenesis act as physiological stimuli that activate both skeletal muscle and liver. This activation triggers a cascade of molecular events, including the upregulation of FNDC5, PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), and the p38 MAPK (mitogen-activated protein kinase) pathway. These molecules play key roles in energy metabolism, mitochondrial biogenesis, and thermogenic responses, contributing to improved metabolic health and adaptive responses to environmental and physical stress.

2.Irisin secretion: These signals promote the secretion of irisin, a myokine, into the blood stream

3.Irisin’s action on adipose tissue: Irisin, a myokine released from skeletal muscle, primarily targets white adipose tissue (WAT). Upon reaching WAT, irisin induces a process known as browning, wherein white fat cells acquire characteristics of brown adipose tissue (BAT). This conversion enhances mitochondrial activity and promotes thermogenesis, thereby increasing energy expenditure and contributing to improved metabolic function and resistance to obesity

4.Brown adipose tissue (BAT): Brown adipose tissue (BAT) is characterized by the presence of lipid droplets and a high density of iron-containing mitochondria, which give BAT its distinctive colour. A key feature of these mitochondria is the presence of uncoupling protein 1 (UCP1), a membrane protein that plays a crucial role in thermogenesis. UCP1 enables the mitochondria to generate heat by uncoupling oxidative phosphorylation, thereby dissipating energy as heat instead of storing it as fat. This process is vital for maintaining body temperature, especially in response to cold exposure.               

5. UCP1 and thermogenesis:  UCP1 uncouples the usual process of energy production in mitochondria, instead generating heat. This process in known as ‘thermogenesis’, and it plays a major role in fat burning.

6. Effects on metabolism: An increase in glucose and lipid uptake by tissues enhances the efficiency of cellular energy production, thereby promoting better metabolism. This improved metabolic activity supports the body's ability to utilize nutrients more effectively, which in turn leads to a rise in energy expenditure. As a result, the body burns more calories, contributing to improved energy balance and potentially aiding in the prevention or management of metabolic disorders such as obesity and type 2 diabetes.            

7. Body mass reduction: As a result of the increased thermogenesis, energy expenditure, and fat conversion processes, the outcome is “weight loss and body mass reduction”.[7]

5.Central Molecule: Irisin

A. Bone: Irisin has been shown to play a crucial role in bone health by stimulating osteoblast proliferation and differentiation through the p38 and ERK signalling pathways. At the same time, it reduces osteoclast number and activity, which contributes to the preservation of bone by decreasing bone resorption. These effects lead to improvements in cortical bone mineral density, thickness, and mechanical strength. Moreover, irisin has the ability to restore bone mass in cases of immobilization-induced osteoporosis, making it a potential therapeutic target. Notably, low levels of irisin have been observed in patients with osteoporosis or osteopenia, highlighting its significance in maintaining bone integrity.[8]

B. Brain (neurocognition and neuroprotection): Irisin plays a significant role in brain health by stimulating the expression of brain-derived neurotrophic factor (BDNF), which enhances synaptic plasticity, memory formation, and hippocampal neurogenesis. Beyond its cognitive benefits, irisin also exhibits neuroprotective effects by protecting neurons from ischemia-induced oxidative stress and apoptotic damage, primarily through the suppression of reactive oxygen species (ROS) and the NLRP3 inflammasome pathway. Additionally, it supports the survival of dopaminergic neurons in models of Parkinson’s disease (PD). Due to these anti-inflammatory and antioxidant mechanisms, irisin shows promising potential as a therapeutic agent for stroke, Alzheimer’s disease, and Parkinson’s disease. [9]

C. Pancreas (beta-cell protection and diabetes): Irisin plays a protective and regulatory role in glucose metabolism by safeguarding pancreatic β-cells from apoptosis and promoting their proliferation and functional capacity, thereby enhancing insulin secretion. Reduced levels of circulating irisin have been strongly associated with type 2 diabetes, indicating its potential involvement in disease progression. In diabetic models, irisin has been shown to lower HbA1c levels and reduce the accumulation of advanced glycation end-products (AGEs), effects that are believed to be mediated through BDNF signalling and improved metabolic regulation. These findings highlight irisin’s therapeutic potential in managing and possibly preventing type 2 diabetes.[10]

D. liver (lipid metabolism and NAFLD) 

Anti-steatosis effects (fat reduction): Irisin plays a key role in regulating liver metabolism and combating fatty liver disease through multiple mechanisms. Firstly, it inhibits de novo lipogenesis (DNL) by suppressing the activity of enzymes responsible for triglyceride synthesis, thereby reducing hepatic fat accumulation. Secondly, irisin promotes glycogen storage and enhances fatty acid oxidation in hepatocytes. It increases glycogen synthesis, suppresses gluconeogenesis, and stimulates lipid breakdown by activating crucial metabolic pathways such as AMPK/mTOR and PI3K/Akt. Additionally, irisin helps protect the liver from oxidative stress and excess fat buildup by inhibiting protein arginine methyltransferase activity, which contributes to reduced lipogenesis and oxidative damage in fatty liver conditions.

Mechanisms of anti-inflammatory: Irisin exerts strong anti-inflammatory effects in the liver, making it a promising candidate for the treatment of non-alcoholic fatty liver disease (NAFLD). It reduces hepatic inflammation by blocking the MD2-TLR4 signalling pathway, a key mediator of immune activation in NAFLD. Irisin disrupts the formation or function of the MD2/TLR4 complex, thereby preventing the downstream activation of pro-inflammatory pathways such as MAPK and NF-ΚB. Additionally, irisin inhibits the activation of the NLRP3 inflammasome in lipopolysaccharide (LPS)-induced models, resulting in reduced production of IL-1β and suppression of hepatic inflammatory cascades. Furthermore, irisin helps resolve liver inflammation by promoting a shift in macrophage polarization toward the anti-inflammatory M2 phenotype. This shift is accompanied by increased release of the anti-inflammatory cytokine IL-10 and suppression of TLR4/NF-ΚB signalling, further contributing to the mitigation of liver inflammation. [12].

Anti-oxidant and anti-ferroptosis actions: Irisin strengthens the liver’s antioxidant defence mechanisms, offering protection against oxidative damage and ferroptosis. It enhances the activity of key antioxidant enzymes such as glutathione peroxidase 4 (GPX4) and increases intracellular glutathione levels, which together help mitigate lipid peroxidation and prevent ferroptosis in hepatocytes. Additionally, irisin reduces the production of reactive oxygen species (ROS) and oxidative stress markers. In animal models, it has been shown to lower malondialdehyde levels—a marker of lipid peroxidation—while boosting the activity of antioxidant enzymes like superoxide dismutase (SOD) and glutathione-S-transferase (GST), further highlighting its protective role in maintaining liver health. [13]

Protecting the liver and preventing fibrosis

Fibrogenesis-related: Elevated levels of irisin observed in patients with fibrotic non-alcoholic fatty liver disease (NAFLD) suggest that it may act as a protective response to liver damage. In experimental models of toxic liver injury, irisin has been shown to inhibit fibrotic signalling by suppressing key inflammatory mediators and blocking the TGF-β pathway, a central driver of liver fibrosis. This inhibition results in reduced collagen deposition and decreased activation of hepatic stellate cells, which are primarily responsible for extracellular matrix production during fibrosis. These findings highlight irisin’s potential role in preventing or attenuating liver fibrosis in chronic liver diseases. [14].

E. The defense system: Irisin exhibits potent anti-inflammatory effects across multiple organs by targeting key inflammatory pathways. It inhibits the nuclear translocation of NF-ΚB, thereby suppressing the expression of pro-inflammatory cytokines such as TNF-α and IL-6, as well as reducing the generation of reactive oxygen species (ROS). Additionally, irisin decreases the activation of the NLRP3 inflammasome and the subsequent release of IL-1β in both macrophages and microglial cells. These actions collectively contribute to a broad anti-inflammatory effect, leading to reduced inflammation in critical organs including the arteries, liver, pancreas, and brain, highlighting irisin's therapeutic potential in systemic inflammatory and metabolic disorders.

6. Effect of Irisin on Muscle

1. Induction and release: Exercise, particularly resistance or endurance training, significantly increases the expression of PGC-1α in muscle tissue. PGC-1α, a key regulator of energy metabolism, in turn stimulates the expression of the FNDC5 gene. Once FNDC5 is synthesized, it undergoes proteolytic cleavage, resulting in the release of irisin into the bloodstream. Irisin is a myokine believed to play an important role in energy expenditure and metabolic health.[15]

Mechanism of Action on Muscle

 2. Irisin Receptors (Integrin αV/β5): Irisin binds to integrin αV/β5 receptors located on the surface of myocytes (muscle cells), initiating a series of intracellular signalling cascades. These signalling pathways are crucial for promoting muscle growth, enhancing metabolic activity, and supporting tissue regeneration, thereby contributing to overall muscle health and function.[16]

3. Muscle Hypertrophy (Growth): Pathways involved: Irisin exerts significant effects on skeletal muscle through multiple intracellular signalling pathways. In the MAPK/ERK signalling pathway, irisin binds to integrin αV/β5, leading to the activation of ERK1/2, which enhances muscle protein synthesis and promotes myoblast proliferation and differentiation, resulting in increased myotube formation. Through the PI3K/Akt/mTOR pathway, irisin activates Akt, which in turn stimulates mTOR (mammalian target of rapamycin), a key regulator of protein synthesis and muscle hypertrophy. Additionally, irisin activates the AMPK pathway, which plays a crucial role in enhancing mitochondrial biogenesis, glucose uptake, and fatty acid oxidation, thereby improving muscle metabolism and endurance. [17],[18]

4.Anti-atrophic Effects (Muscle Preservation): Irisin plays a protective role in muscle maintenance by downregulating muscle-specific ubiquitin ligases such as MuRF1 and Atrogin-1, which are key enzymes involved in protein degradation. By suppressing the activity of these ligases, irisin helps prevent muscle wasting, particularly during periods of aging or disuse, such as immobilization or inactivity.[19]

5. Muscle Regeneration: Irisin enhances the activation of satellite cells, which are muscle stem cells essential for muscle repair and regeneration. In addition, it stimulates the expression of myogenic transcription factors such as MyoD and myogenin, which are critical for initiating and promoting the formation of new muscle fibres. Through these mechanisms, irisin supports muscle growth and recovery following injury or physical exertion. [20]

6. Improved Mitochondrial Function: Irisin increases the expression of PGC-1α and mitochondrial proteins such as UCP1 in muscle tissue, thereby enhancing the muscle’s oxidative capacity. This improvement in mitochondrial function leads to several beneficial effects, including better endurance, delayed onset of fatigue, and increased fat oxidation during physical activity. These adaptations contribute to improved overall performance and metabolic efficiency. [21]

7. Irisin and Cardiovascular Health

Irisin, a myokine cleaved from the membrane protein FNDC5, has emerged as a key player in the regulation of cardiovascular function. Beyond its role in energy metabolism and adipose browning, irisin has been shown to have direct and indirect effects on the cardiovascular system, including vascular function, cardiac remodelling, blood pressure regulation, and atherosclerosis. This makes irisin a promising target for preventing and managing cardiovascular diseases (CVDs), particularly those linked to metabolic syndromes such as obesity and diabetes.

A. Effects on Endothelial Function: Irisin plays a vital role in maintaining vascular health by improving endothelial cell function, a key factor in regulating blood vessel tone and circulation. It promotes the production of nitric oxide (NO), a potent vasodilator, through the activation of the AMPK-eNOS signalling pathway. Mechanistically, irisin activates AMP-activated protein kinase (AMPK), which subsequently enhances the phosphorylation and activity of endothelial nitric oxide synthase (eNOS). This leads to an increase in NO bioavailability, resulting in vasodilation and improved blood flow, thereby supporting cardiovascular function and reducing the risk of vascular diseases. [22]

B. Anti-Atherosclerotic Properties:

Atherosclerosis is a chronic inflammatory disease characterized by the buildup of plaques within the arterial walls. Irisin has demonstrated protective effects against atherosclerosis by inhibiting the expression of adhesion molecules such as VCAM-1 and ICAM-1, which are crucial for the recruitment of inflammatory cells to the vascular endothelium. The underlying mechanism involves downregulation of the NF-ΚB signalling pathway and a reduction in oxidative stress, both of which contribute to a decreased inflammatory response in vascular cells. Through these actions, irisin helps to prevent vascular inflammation and plaque formation, offering potential therapeutic value in cardiovascular disease prevention. [23]

C. Control of Blood Pressure: Irisin plays a role in the regulation of blood pressure by influencing multiple physiological mechanisms, including salt balance, endothelial function, and vascular tone. Studies have shown that irisin infusion can lead to a reduction in systolic blood pressure in hypertensive animal models. This antihypertensive effect is believed to occur through the reduction of oxidative stress and the modulation of the renin-angiotensin system (RAS), both of which are key contributors to the development and maintenance of high blood pressure. These findings suggest that irisin may have therapeutic potential in managing hypertension. [24]

D. Protection and Remodelling of the Heart: Cardiac remodelling is a hallmark of heart failure and post-infarction injury, characterized by structural and functional changes in the heart. Irisin has shown protective effects against such cardiac damage, including ischemia-reperfusion injury, fibrosis, and cardiomyocyte death. Mechanistically, irisin reduces oxidative stress, activates protective signalling pathways such as PI3K/Akt and ERK1/2, and inhibits the expression of fibrotic markers like TGF-β1 and collagen I/III, thereby preventing pathological remodelling of cardiac tissue. Moreover, irisin has emerged as a promising biomarker in cardiovascular disease (CVD). Several studies have identified reduced circulating levels of irisin in patients with conditions such as coronary artery disease (CAD), heart failure, and hypertension. Its levels may reflect early endothelial dysfunction and metabolic abnormalities, both of which contribute to CVD progression. Supporting this, a meta-analysis by Qiu et al. (2016) found a significant association between low irisin levels and increased risk of CVD, particularly among obese and diabetic individuals, highlighting its potential as a diagnostic and prognostic marker in cardiovascular health. [25]

8. Potential And Difficulties for Therapy

Irisin is currently being explored as a therapeutic agent or target in the treatment of cardiovascular diseases (CVDs) due to its demonstrated cardioprotective properties, including anti-inflammatory, antioxidant, and anti-fibrotic effects. However, several challenges hinder its clinical application. These include irisin's short half-life and limited stability in circulation, the lack of a clearly identified receptor, and the need for optimizing its dosage for effective and safe medicinal use. To overcome these limitations, researchers are focusing on developing irisin analogues or small molecules that mimic its biological functions. Such advancements could pave the way for novel therapeutic strategies in the management of cardiovascular diseases.

9. Irisin in Cancer

Irisin, a hormone-like myokine secreted predominantly by skeletal muscle in response to physical exercise, has gained attention for its potential anticancer properties. Although originally identified for its role in metabolism and adipose tissue browning, irisin also exerts anti-proliferative, pro-apoptotic, anti-inflammatory, and anti-metastatic effects in several types of cancers. However, context-dependent effects have also been observed, with some studies reporting pro-cancer effects under certain conditions.

1. Mechanisms of Irisin's Anti-Cancer Effects: Irisin has shown promising anticancer potential through several molecular mechanisms that influence tumour biology. It helps prevent cancer cell proliferation by suppressing key oncogenic signalling pathways, including PI3K/Akt/mTOR, STAT3, and NF-ΚB, which are often overactivated in cancer to support cell survival and growth. In addition, irisin promotes apoptosis by downregulating anti-apoptotic proteins like Bcl-2 and upregulating pro-apoptotic markers such as Bax and cleaved caspase-3. It also induces cell cycle arrest, typically in the G0/G1 or G2/M phases, thereby halting tumour progression. Furthermore, irisin exhibits anti-metastatic effects by enhancing E-cadherin expression and suppressing transcription factors like Snail and Twist, which are key mediators of the epithelial–mesenchymal transition (EMT). Additionally, irisin contributes to a less inflammatory tumour microenvironment by inhibiting the NF-ΚB pathway and reducing pro-inflammatory cytokines such as TNF-α and IL-6.[26], [27]

2.Evidence from specific cancer types: Supports these findings. In breast cancer, irisin inhibits proliferation and invasion of MDA-MB-231 and MCF-7 cells while promoting apoptosis. In colon cancer, it reduces cell viability and colony formation and downregulates β-catenin, a key player in the WNT signalling pathway. In lung cancer, particularly A549 cells, irisin suppresses migration, EMT, and proliferation by enhancing E-cadherin expression and inhibiting the PI3K/Akt pathway. In pancreatic cancer, irisin affects PANC-1 cells by reducing cell division, inducing apoptosis, altering caspase activity, and modulating mitochondrial membrane potential. In osteosarcoma, it interferes with the MAPK and mTOR pathways, thereby limiting the growth and migration of cancer cells. Collectively, these findings highlight irisin’s multifaceted role in cancer suppression and its potential as a therapeutic target in oncology. [28],[29],[30]

3. Cancer Patients' Serum Irisin Levels: Although results are conflicting, clinical research has revealed that cancer patients have changed serum irisin levels. According to certain research, newly diagnosed cancer patients (such as those with breast or gastrointestinal tumours) have greater levels of irisin, maybe as a compensating reaction. Others discovered reduced irisin levels, especially in patients who had cachexia or advanced malignancies.[31]

4. Irisin and Treatment for Cancer: Irisin has the potential to be used as an adjuvant therapy, particularly in exercise-oncology, where it may work in concert with conventional treatments. For medicinal purposes, some researchers are investigating irisin mimetics or analogues. Irisin may lessen cachexia brought on by chemotherapy and increase chemosensitivity. Caution: According to certain in vitro research, irisin may increase survival in particular tumour contexts (for example, because of metabolic adaptation), necessitating context-specific analysis.

10. Irisin in Longevity and Aging

A myokine that is mostly released by skeletal muscles in reaction to exercise, irisin has been more connected to longevity and anti-aging benefits. It has protective effects on oxidative stress, inflammation, neurodegeneration, cellular senescence, mitochondrial function, and other basic biological aging processes.

A. Cellular Senescence and Irisin: Irisin exerts its anti-aging effects by modulating key cellular mechanisms associated with senescence. It decreases the activity of senescence-associated β-galactosidase (SA-β-gal), a widely used marker of cellular aging. Additionally, irisin influences critical aging-related signalling pathways, including p16^INK4a and p53/p21, which are known to regulate cell cycle arrest and senescence. By doing so, it helps maintain cellular proliferative capacity and prevents telomere shortening—an essential factor in cellular longevity. Supporting evidence shows that irisin enhances nitric oxide bioavailability and reduces oxidative stress-induced senescence in human umbilical vein endothelial cells (HUVECs), further demonstrating its protective role in vascular aging. [32]

B. Irisin and Neuroprotection/Cognitive Aging: Irisin plays a crucial role in neuroprotection by increasing the levels of brain-derived neurotrophic factor (BDNF), a key protein essential for memory formation and learning. Importantly, irisin is capable of crossing the blood–brain barrier, allowing it to exert direct effects within the brain. It reduces the accumulation of amyloid-β plaques and neuroinflammation, both of which are hallmark features of Alzheimer’s disease. Furthermore, irisin supports neurogenesis in the hippocampus and enhances synaptic plasticity, which are vital for maintaining cognitive function. Experimental evidence has shown that irisin elevated BDNF expression in the hippocampus of aged mice, resulting in improved memory and cognitive performance. Notably, cognitive decline associated with aging was reversed through exercise-induced irisin, highlighting its therapeutic potential in age-related neurodegenerative conditions. [33]. 

C. Mitochondrial Health and Irisin: Irisin enhances mitochondrial health by upregulating the expression of PGC-1α, a key regulator of mitochondrial biogenesis. This leads to an increase in the number and efficiency of mitochondria, which is essential for maintaining cellular energy production. Irisin also reduces the levels of reactive oxygen species (ROS) and helps preserve mitochondrial membrane potential, both of which are critical for preventing oxidative damage and maintaining mitochondrial integrity. These actions collectively improve energy metabolism and mitigate aging-related mitochondrial dysfunction. Supporting evidence shows that irisin significantly improves mitochondrial function and alleviates age-related sarcopenia in aged skeletal muscle, demonstrating its potential in preserving muscle health during aging.[34]

 D. Irisin and Inflammaging: Irisin exhibits strong anti-inflammatory properties by suppressing the production of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). It achieves this effect primarily through the inhibition of the NF-ΚB signalling pathway, which plays a central role in regulating chronic inflammation. By dampening this pathway, irisin helps reduce the persistent low-grade inflammation often associated with aging, thereby preventing tissue damage and promoting cellular health. Experimental studies in aged mice and macrophage models have shown that irisin treatment significantly decreased systemic inflammation and improved overall tissue homeostasis, highlighting its therapeutic potential in age-related inflammatory conditions. [35]

E. Irisin and Muscle Aging (Sarcopenia): Irisin supports muscle health and regeneration by modulating key genes involved in muscle development and atrophy. It increases the expression of myogenic factors such as MyoD and myogenin, which are essential for muscle differentiation and repair. Simultaneously, it downregulates muscle atrophy-related genes like myostatin and MuRF1, which are known to promote muscle degradation. These combined actions enhance muscle strength and regenerative capacity, particularly in aged individuals. Evidence from experimental models shows that exercise-induced irisin effectively prevents age-related muscle mass loss and significantly boosts the muscle’s ability to regenerate, underscoring its therapeutic promise in combating sarcopenia and muscle degeneration associated with aging. [36]

F. Irisin and Longevity Pathways: Irisin contributes to healthy aging by activating key longevity-associated genes such as SIRT1, AMPK, and FOXO3a. These genes play critical roles in cellular energy balance, stress resistance, and lifespan regulation. Irisin also promotes autophagy and proteostasis—processes vital for the clearance of damaged cellular components and maintenance of protein quality, which are often impaired during aging. Additionally, it enhances the Nrf2-mediated antioxidant response, thereby reducing oxidative stress and protecting cells from age-related damage. Evidence from cellular studies demonstrates that irisin upregulates the expression of SIRT1 and AMPK, mimicking the beneficial effects of caloric restriction, a well-known intervention for extending lifespan and improving cellular health. [37]

11.Irisin Therapeutic Applications and Drug Development Potential

1. Neurodegenerative Diseases: The therapeutic potential of the compound lies in its ability to enhance brain-derived neurotrophic factor (BDNF) expression and support synaptic plasticity, both of which are crucial for maintaining cognitive function and neuronal health. Additionally, it reduces the accumulation of amyloid-beta (Aβ) and the phosphorylation of tau proteins—two hallmark pathological features of Alzheimer’s disease. Notably, it is capable of crossing the blood-brain barrier (BBB), which makes it a promising candidate for neurotherapeutic applications. Due to these properties, it is being explored as a potential treatment for neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). [38]

2. Cardiovascular Diseases (CVD): The therapeutic potential of the compound is evident in its ability to improve endothelial function and maintain vascular homeostasis, which are essential for cardiovascular health. It effectively reduces atherosclerosis, myocardial fibrosis, and oxidative stress—key contributors to cardiovascular disease progression. Moreover, it stimulates angiogenesis through the activation of the AMPK-eNOS signalling pathway, promoting new blood vessel formation and improved tissue perfusion. These combined effects make it a promising candidate for the treatment of hypertension, heart failure, and atherosclerosis. [39]

3. Metabolic Syndrome and Obesity: The compound shows strong potential for therapy by promoting the browning of white adipose tissue (WAT), a process where WAT is transformed into brown-like adipose tissue (BAT). This transformation enhances thermogenesis through the upregulation of uncoupling protein 1 (UCP1), leading to increased energy expenditure. Additionally, it contributes to a reduction in hepatic steatosis and improves insulin sensitivity, both of which are critical in metabolic health. These effects make it a promising therapeutic candidate for the management of Type 2 Diabetes Mellitus (T2DM), overweight or obesity, and non-alcoholic fatty liver disease (NAFLD). [40]

4. Treatment for Cancer: The compound exhibits significant potential for cancer therapy by inhibiting epithelial-mesenchymal transition (EMT), angiogenesis, and overall tumour growth. It induces apoptosis in various types of cancer cells, thereby limiting tumour progression. Its therapeutic effects are mediated through the regulation of key signalling pathways, including MAPK, STAT3, and PI3K/Akt, which are commonly dysregulated in cancer. Due to these multifaceted actions, it holds promise in the treatment of several cancers, including those of the pancreas, liver, colon, lung, breast, and osteosarcoma. [41]

5. Sarcopenia and Aging: The compound demonstrates promising therapeutic potential in reversing age-related muscle loss by targeting key mechanisms involved in aging and muscle degeneration. It effectively reduces inflammation and enhances mitochondrial biogenesis, supporting improved cellular energy production and muscle function. Additionally, it activates SIRT1-linked pathways associated with longevity and promotes autophagy, aiding in the removal of damaged cellular components. These combined effects make it a valuable candidate for anti-aging treatments and for managing disorders related to geriatric muscular atrophy.[42]

6. Strategies for Drug Development

A. Irisin Recombinant: Both in vitro and in vivo tests have been performed on recombinant irisin protein. Obstacles include limited stability, bioavailability, and short half-life [43].

B. Peptidomimetics and Irisin Mimetics: creating artificial irisin analogy or mimetics in order to preserve function while improving pharmacological characteristics.

Present Situation: Drugs based on irisin are still in the preclinical stage and have not yet received FDA approval.

c. Delivery Systems and Gene Therapy: Delivering FNDC5 or irisin peptides to specific tissues via viral vectors or nanoparticles. Using CRISPR-Cas9 or AAV vectors, tissue-specific expression is being developed. [44]                                                                                                            

12. CONCLUSION

Irisin, a novel exercise-induced myokine, has emerged as a multifunctional hormone with promising therapeutic potential across a wide spectrum of physiological systems and pathological conditions. Originally discovered for its role in converting white adipose tissue to a brown fat-like phenotype, irisin has since been implicated in modulating energy metabolism, reducing inflammation, enhancing neurogenesis, preventing cardiovascular damage, countering cancer progression, delaying aging, and improving skeletal muscle health. Mechanistically, irisin exerts its effects through a range of signalling pathways, including AMPK, PGC-1α, SIRT1, PI3K/Akt, MAPK, NF-κB, and STAT3, among others. Its ability to cross the blood-brain barrier and influence central nervous system function further broadens its therapeutic scope. Despite its immense potential, the clinical translation of irisin is still in its infancy. Key challenges remain, such as understanding its receptor(s), pharmacokinetics, tissue-specific actions, and long-term safety in humans. Advances in recombinant irisin production, mimetic development, and targeted delivery systems are critical steps toward realizing its therapeutic promise. In summary, irisin represents a compelling target for drug development, with the capacity to bridge lifestyle interventions like exercise and molecular therapies. Further research and clinical trials are essential to validate irisin as a viable therapeutic agent and to fully harness its multifaceted benefits in human health and disease.

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