Front. Med.Frontiers in MedicineFront. Med.2296-858XFrontiers Media S.A.10.3389/fmed.2024.1502368MedicineReviewThe potential therapeutic role of melatonin in organ fibrosis: a comprehensive reviewHuangWei12†ZhengJuan1†WangMing12DuLing-Yao12BaiLang12*TangHong12*1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China2Laboratory of Infectious and Liver Diseases, Institute of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
Edited by: Yan-Ling Wu, Yanbian University, China
Reviewed by: Ratnakar Tripathi, University of Missouri, United States
Lorenzo Franceschetti, University of Milan, Italy
*Correspondence: Lang Bai, pangbailang@163.com; Hong Tang, tanghong6198@wchscu.cn
†These authors have contributed equally to this work
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Organ fibrosis is a pathological process characterized by the inability of normal tissue cells to regenerate sufficiently to meet the dynamic repair demands of chronic injury, resulting in excessive extracellular matrix deposition and ultimately leading to organ dysfunction. Despite the increasing depth of research in the field of organ fibrosis and a more comprehensive understanding of its pathogenesis, effective treatments for fibrosis-related diseases are still lacking. Melatonin, a neuroendocrine hormone synthesized by the pineal gland, plays a crucial role in regulating biological rhythms, sleep, and antioxidant defenses. Recent studies have shown that melatonin may have potential in inhibiting organ fibrosis, possibly due to its functions in anti-oxidative stress, anti-inflammation, remodeling the extracellular matrix (ECM), inhibiting epithelial-mesenchymal transition (EMT), and regulating apoptosis, thereby alleviating fibrosis. This review aims to explore the therapeutic potential of melatonin in fibrosis-related human diseases using findings from various in vivo and in vitro studies. These discoveries should provide important insights for the further development of new drugs to treat fibrosis.
melatoninfibrosistherapeuticsprotective effectsmechanisms2022YFC2304800ZYJC21014National Key Research and Development Program of China10.13039/5011000121661.3.5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan Universitysection-at-acceptanceHepatobiliary DiseasesIntroduction
Organ fibrosis is the ultimate outcome of various chronic diseases, characterized by the deposition of extracellular matrix (ECM) leading to scar tissue formation as the primary pathological change (1). Continuous progression can result in structural damage and loss of function in organs, ultimately leading to death, as seen in end-stage liver, kidney, lung, and heart diseases (2). Organ fibrosis significantly impacts global morbidity and mortality rates. In developed countries, nearly 45% of human deaths are associated with fibrosis-related diseases, and this proportion may be even higher in developing countries (3). Despite ongoing research into the occurrence and development of fibrosis, current methods for anti-fibrotic treatment are limited and often ineffective, making it crucial to search for effective therapeutic approaches.
Melatonin (N-Acetyl-5-methoxytryptamine) is a methoxylated indole produced in peripheral tissues such as the retina, gastrointestinal tract and bone marrow and primarily synthesized and secreted by the pineal gland under normal light–dark conditions during the night in vertebrates (4). Melatonin was first isolated from the bovine pineal gland by Lerner et al. (5). Melatonin synthesis begins with the hydroxylation of tryptophan to form 5-hydroxytryptophan, followed by decarboxylation to produce 5-hydroxytryptamine (5-HT). This is then acetylated to form N-acetyl-5-hydroxytryptamine, which is finally methylated to produce N-acetyl-5-methoxytryptamine (6). The production of melatonin is typically influenced by various factors, and it is currently understood that the secretion rhythm of melatonin relies on an intrinsic circadian structure triggered by light signals received by the retina. This rhythm originates from the suprachiasmatic nucleus (SCN), where light exposure transmits neural impulses to the SCN via the retinohypothalamic tract, synchronizing the activity of the SCN and the nocturnal secretion rhythm of melatonin with the 24-h light/dark cycle. Norepinephrine (NE) serves as a mediator in the effect of light on melatonin synthesis and secretion. Light can inhibit the release of NE through specific pathways, whereas in darkness, sympathetic neuronal activity within the pineal gland significantly increases, resulting in higher NE release. NE binds to receptors on the pineal gland cell membrane, promoting the entry of tryptophan into the cells. Once NE binds to its receptors, cyclic adenosine monophosphate (cAMP) facilitates the synthesis of serotonin and melatonin (7). Additionally, light is an important external factor influencing melatonin secretion. Various non-environmental factors, such as sleep quality and duration, hunger, and physical activity, may also affect melatonin secretion (8–10).
After melatonin is synthesized, it is immediately released into the cerebrospinal fluid and blood, distributing throughout the body via systemic circulation. Its plasma concentration exhibits a distinct circadian rhythm, being higher at night than during the day (11). Based on the affinity for binding sites, melatonin receptors can be classified into three subtypes: melatonin receptor 1A (MT1) (12), melatonin receptor 1B (MT2) (13), and melatonin receptor 1C (MT3) (14). As members of the G protein-coupled receptor superfamily, MT1 and MT2 are both primarily located in the brain and other extra-pineal tissues, including the liver, skeletal muscle, and retina. MT3 is found in the liver, kidneys, heart, adipose tissue, and brain (15). By binding to different melatonin receptors, melatonin rapidly activates various signal transduction cascades, thereby exerting its biological effects in the body. Melatonin is widely recognized as a potent antioxidant and is also involved in mediating various biological effects such as anti-inflammatory responses, circadian rhythms, cellular metabolism, and immune regulation (16). Recent research suggests that exogenous melatonin supplementation can alleviate organ fibrosis, including liver fibrosis, lung fibrosis, heart fibrosis, and kidney fibrosis, indicating that melatonin may be a potential anti-fibrotic agent.
This review begins by outlining the process of liver fibrosis development. It then summarizes the possible mechanisms by which melatonin inhibits fibrosis development. Finally, it discusses the roles melatonin may play in different organ fibrosis scenarios. It is hoped that this article will provide a new perspective for subsequent experimental research and offer more theoretical support for the clinical recommendation and widespread application of melatonin.
Pathogenesis of organ fibrosis
Typically, when tissue is injured, wound healing undergoes three main phases: the inflammatory phase, the proliferative phase, and the remodeling/maturation phase (2, 17). These phases serve different functions and overlap in time (18) (Figure 1).
The primary synthesis process and anti-fibrotic effects of melatonin after organ injury, the damaged cells secrete chemokines and cytokines, recruiting and activating inflammatory cells such as macrophages, monocytes, and lymphocytes. The signals released by these cells activate fibroblasts, which then transform into myofibroblasts and synthesize extracellular matrix (ECM). Chronic injury and inflammation lead to persistent myofibroblast activation, excessive ECM deposition, and ultimately fibrosis. Red blunted line: an inhibitory effect of melatonin.
Under normal circumstances, after an injury, the formation of a platelet plug and provisional ECM stops the bleeding, accompanied by an increased threshold of the inflammatory response and recruitment of immune cells. This process initiates the first phase of healing, the inflammatory phase. During this phase, a large number of neutrophils and macrophages infiltrate the tissue to combat potential infection and clear debris (19). In the inflammatory phase, damaged endothelial/epithelial cells and myofibroblasts produce aberrant matrix metalloproteinases (MMPs), disrupting the basement membrane of local tissues and releasing various cytokines and chemokines, thereby recruiting and activating more immune cells, including neutrophils, macrophages, T lymphocytes, and B lymphocytes (3, 20).
Activated leukocytes release mediators such as pro-inflammatory, vasoactive, and pro-fibrotic effectors, inducing precursor cells to differentiate into myofibroblasts. Myofibroblasts rapidly produce large amounts of ECM to maintain the integrity of damaged tissue during the repair process and promote cell proliferation to form granulation tissue. Myofibroblasts are the primary effector cells in fibrosis (21).These cells can secrete large amounts of ECM proteins (mainly collagen I, collagen III, and fibronectin), increase the production of tissue inhibitors of metalloproteinases, and express alpha smooth muscle actin (α-SMA), which confers contractility (22, 23). The sources of myofibroblasts may vary across different tissues. Currently, it is believed that the activation of resident fibroblasts in the tissue is the main source of myofibroblasts (24). Under certain conditions, epithelial and endothelial cells also can differentiate into myofibroblasts through epithelial/endothelial-mesenchymal transition (EMT/EndoMT) (25–27), and mesothelial cells can differentiate into myofibroblasts through mesothelial-mesenchymal transition (28, 29).
In the final tissue remodeling/maturation phase, activated myofibroblasts cause wound contraction; dynamic ECM degradation and remodeling restore the parenchymal tissue structure. However, persistent inflammation, necrotic cells, ongoing fibroblast activation, and excessive ECM deposition lead to abnormal tissue reconstruction, resulting in organ fibrosis.
To date, various mediators have been identified that can activate fibroblasts and promote the occurrence and progression of fibrosis, including transforming growth factor-β (TGF-β) (30), interleukins (IL-1β, IL-6, IL-13, IL-33, IL-11, IL-17, etc.), tumor necrosis factor-α (TNF-α), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF) (31), angiotensin-II (Ang-II) (32), heat shock protein (33), endothelin-1 (34), integrins (35), reactive oxygen species (ROS), and hypoxia. TGF-β is a cytokine with diverse physiological functions, playing a key role in regulating cell proliferation, differentiation, apoptosis, and immune responses (36). Currently, three isoforms of TGF-β are known: TGF-β1, TGF-β2, and TGF-β3. Among these, TGF-β1 is the most abundant isoform in humans, widely expressed in most cell types, with platelets serving as a significant source (37). Although these three isoforms share similar bioactive regions and can bind to the same type I and type II TGF-β receptor complexes, TGF-β is widely recognized as the most potent pro-fibrotic factor, primarily acting through the Smad (Smad-2, −3, −4, etc.) signaling pathway to promote fibrosis development (38, 39). In addition, TGF-β can also facilitate fibrosis through multiple non-Smad-dependent pathways, such as those involving c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK1/2), and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) or Rho-like GTPases (30, 40). During TGF-β signaling, activated Smad complexes can induce the expression of various transcription factors in the nucleus, thereby promoting the activation of fibroblasts. Research indicates that the Smad pathway can induce the expression of the JunD transcription factor, and knocking out this gene results in a reduction in the number of myofibroblasts and decreased collagen release (41). Additionally, the Smad pathway interacts with the Snail family of transcription factors (42) and zinc finger E-box-binding homeobox (ZEB) transcription factor family to enhance myofibroblast differentiation through EMT (43). IL-1β-treated fibroblasts differentiate into myofibroblasts, leading to increased ECM deposition. IL-13 promotes liver fibrosis formation by directly inducing the expression of liver fibrosis-related genes such as collagen and CTGF. TNF-α is a critical inflammatory signal molecule in fibrosis, mainly secreted by macrophages. By binding to specific receptors, TNF-α initiates signal cascades, activating nuclear factor-kappa B (NF-κB) to regulate inflammatory responses, and triggers cell activation, differentiation, cytokine production, and apoptosis, thus contributing to fibrosis progression. NF-κB is an inducible transcription factor family responsible for regulating the initiation and progression of inflammatory responses. The activation of NF-κB occurs primarily through two pathways: the canonical and the non-canonical pathways. The canonical pathway is activated when signals such as pro-inflammatory cytokines or pathogen-associated molecular patterns activate cell surface receptors, including pattern recognition receptors, Toll-like receptors (TLR), and T cell receptors. In contrast, the non-classical signaling pathway is primarily activated by TNF and its corresponding TNF receptors (44). Studies have shown that during the NF-κB signaling process, its inhibitors can suppress fibroblast activity in a concentration-dependent manner (45).
The mechanisms of melatonin alleviating fibrosis
Melatonin was initially discovered and named for its ability to lighten the skin of amphibians (5, 46). As research progressed, melatonin was identified as a lipid-soluble hormone that can act on almost every cell in the organism, crossing all biological barriers. Its primary function is to regulate and reset circadian rhythms (47), but it also has anti-cancer (48), immune-modulating (49) and many other functions. Melatonin exerts its anti-fibrotic effects, and the mechanisms may involve reducing oxidative stress, inhibiting inflammatory responses, ECM remodeling, suppressing EMT, and preventing apoptosis (Figure 2).
The biological effects of melatonin and common organ fibrosis. ROS, reactive oxygen species; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition.
Antioxidant stress
Oxidative stress arises from cells’ inefficient utilization of molecular oxygen (50). ROS include superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and singlet oxygen, which are byproducts of cellular respiration and other metabolic processes (51). Additionally, there are highly destructive nitrogen-based substances such as nitric oxide, especially peroxynitrite anion (52). Oxidative stress is considered a major cause of fibrosis as it damages the structures of cellular macromolecules like DNA, proteins, and lipids, ultimately leading to cell damage and promoting fibrosis (53).Studies have shown that melatonin can enhance mitochondrial adenosine triphosphate synthesis and reduce the production of reactive oxygen species (54). Furthermore, melatonin not only directly interacts with various ROS, reactive nitrogen species, and organic radicals to exert a direct scavenging effect, but also upregulates the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione, (GSH), glutathione reductase (GRd), and glucose-6-phosphate dehydrogenase (52, 55). Additionally, melatonin downregulates the activities of pro-oxidant enzymes like nitric oxide synthase (NOS) and lipoxygenase, thereby exerting an indirect antioxidant effect (52). Furthermore, melatonin, similar to metallothioneins, can bind to heavy metals such as aluminum, cadmium, copper, iron, lead, and zinc, thus mitigating oxidative stress (56). As a lipid-soluble free radical scavenger, melatonin can easily cross the blood–brain barrier, replacing or supplementing metallothioneins in the brain as the primary binding agents for transition metals (57).
Anti-inflammation
Recruited inflammatory cells and damaged epithelial cells eventually transform into fibrogenic effector cells or induce the activation of precursor cells, which is a crucial component of the fibrosis process. Recent studies have found that melatonin can inhibit the infiltration of inflammatory cells by reducing myeloperoxidase activity (58, 59). Melatonin effectively lowers the levels of pro-inflammatory factors and fibrosis markers, demonstrating anti-inflammatory activity in various diseases. In human blood cells, melatonin can reduce lipopolysaccharide (LPS)-induced TNF-α levels (60, 61). In patients with osteoarthritis, researchers observed that melatonin effectively inhibits the production of pro-inflammatory cytokines during inflammation by suppressing the Erk and PI3K/Akt signaling pathways, significantly reducing the expression of TNF-α, IL-8, and vascular endothelial growth factor in synovial fibroblasts (62). The NF-κB transcription factor family is considered a central mediator in the inflammatory process (63), and studies have shown that melatonin can inhibit NF-κB signaling and activate the antioxidant regulators nuclear erythroid 2-related factor 2 (Nrf2) (63, 64). Furthermore, melatonin exerts its anti-inflammatory effects by inhibiting the expression of the inflammasome NLR family pyrin domain containing 3 (NLRP3) and the activation of NF-κB while upregulating the expression of the transcription factor Nrf2 (65). Melatonin also significantly reduces the expression levels of nitric oxide and malondialdehyde (MDA), which are closely associated with inflammation (59, 66).
ECM remodeling
Under physiological conditions, the ECM is a highly dynamic structure present in all tissues, constantly undergoing balanced remodeling. This remodeling process is primarily mediated by specific enzymes, particularly MMPs (67). When tissue is damaged, the synthesis and degradation of ECM become progressively imbalanced, eventually leading to ECM deposition and, consequently, tissue fibrosis (68). During ECM deposition, a large amount of MMPs is activated, breaking down the cells and their surrounding basement membrane matrix, allowing leukocytes to migrate into the tissue (69). Additionally, MMPs influence the secretion of various chemokines and cytokines, creating a strong chemokine gradient that leads to the recruitment of inflammatory cells to the site of injury (70, 71). Melatonin has a regulatory effect on MMP gene expression and catalytic activity (72). MMP-9 is a zinc metalloproteinase that, as a matrix protein, is released from intracellular stores and becomes active extracellularly (73, 74). Studies have found that in mice with liver fibrosis treated with melatonin, MMP-9 activity is reduced and Nrf2 expression is increased (75). In gastric adenocarcinoma cell lines, melatonin inhibits both the induction and catalytic activity of MMP-9 (73). Collagen and glycosaminoglycan (GAG) are major components of the ECM, and research has shown that melatonin can effectively reduce the amounts of collagen (76–78) and GAG (79), thereby alleviating tissue fibrosis to some extent.
Anti-EMT
EMT is an important process in normal embryonic development and tissue repair, during which differentiated epithelial cells undergo phenotypic transformation to acquire a mesenchymal phenotype (80). This is a reversible biological process. The EMT process involves the induction and regulation of multiple signal transduction pathways, primarily including TGF-β, NF-κB, Wnt, Notch and et. pathways (67). These pathways converge on the EMT-related transcription factor families, triggering extensive cellular transcriptional reprogramming. The main EMT-related transcription factors include members of the SNAIL, ZEB, TWIST, and PRRX families, as well as various EMT effectors (81). In the context of persistent chronic injury, the role of EMT shifts from promoting tissue repair to contributing to tissue degeneration, leading to irreversible dedifferentiation and cell cycle arrest (82). Moreover, EMT can enhance the secretion of TGF-β and inflammatory cytokines by damaged epithelial cells, which, respectively, promote the differentiation of fibroblasts into myofibroblasts and trigger immune inflammation, ultimately resulting in repair failure and tissue fibrosis (83, 84). Research indicates that melatonin may inhibit the activity of the Notch signaling pathway, thereby blocking the migration, invasion, and EMT of normal and endometriosis epithelial cells induced by 17β-estradiol (85). Research indicates that melatonin can inhibit the secretion of IL-1β, IL-6, and TGF-β induced by LPS both in vivo and in vitro (86). Additionally, melatonin can reverse LPS-induced EMT in peritoneal mesothelial cells by inhibiting the TLR4/ JNK and TLR4/NF-κB-Snail signaling pathways (87).
Regulation of apoptosis
Apoptosis is an orderly process of programmed cell death controlled by genes, involving the activation, expression, and regulation of genes (88). It is a proactive response of cells to adapt to their living environment. The regulation of apoptosis mainly occurs through the intrinsic mitochondrial pathway and the extrinsic death receptor pathway (89). The intrinsic pathway is initiated by the insertion of Bax/Bak into the mitochondrial membrane, followed by the release of cytochrome c (Cyt C) (90). Cyt C then combines with Apaf-1 and procaspase-9 to form the apoptosome, which subsequently activates caspase-3, initiating the apoptotic cascade (91). The extrinsic pathway is triggered by external stimuli or ligand molecules, primarily involving death receptors (92). Research indicates that melatonin can reduce cisplatin-induced apoptosis in renal tubular cells by inhibiting the activation of caspase-3 (93). In thymocytes induced by glucocorticoids, melatonin exerts an anti-apoptotic effect by regulating the levels of Bax protein (94). During fibrosis, the abnormal proliferation of fibrotic effector cells and their resistance to apoptosis are key factors. Interestingly, the regulation of apoptosis by melatonin depends on the cell type. In human hypertrophic scar tissue, melatonin inhibits fibroblast proliferation and induces apoptosis by regulating the gene expression of cyclin E, p53, and Fas (95). The alleviation of fibrosis by melatonin may be related to the reduction of fibroblast migration through decreased chloride channel activity mediated by protein kinase C (96).
Protective effects of melatonin in fibrotic diseases
Numerous studies have shown that melatonin provides comprehensive protection for various organs and tissues, including the heart, lungs, liver, and kidneys, by preventing fibrosis and aiding in the repair of damage to these organs and tissues (Table 1).
Summary of anti-fibrotic effects and underlying mechanisms of melatonin.
Fibrotic disease
Model
Animal/cell type
Effect and mechanism
References
Cardiac fibrosis
High-fat diet and PM2.5
Male ApoE−/− mice
Reversing phenotypic modulation of cardiac fibroblasts into myofibroblasts; ↓mitochondrial ROS generation and oxidative injury; regulating SIRT3-mediated SOD2 deacetylation
Jiang et al. (103)
Ang-II and PM2.5
Embryonic heart fibroblast cell
Streptozotocin
Male KM mice
↓Collagen production; ↓lncR-MALAT1/miR-141-mediated NLRP3 inflammasome activation and TGF-β1/Smads signaling
Che et al. (104)
High-glucose
Cardiac fibroblast
Abdominal aortic constriction
Male SD rat
↓Cross-sectional area of myocardial fibers and collagen deposition; ↓HDAC1-4 and HDAC6 expressions
Wu et al. (106)
High-fat/Streptozotocin and MI surgery
Male C57BL/6 J mice
↓Cardiomyocyte cross-sectional area and interstitial fibrotic area; ↓p53, caspase-3, and Bax levels; ↑Bcl-2 levels; ↓the JNK/p53-mediated apoptotic pathway
Lu et al. (107)
High fat/High glucose and hypoxia
Cardiomyoblast
High-glucose and MI/R surgery
Male SD rat
↓Infarct size, ↓TUNEL-positive myocardial cells and oxidative stress; ↑Notch1/Hes1/Akt signaling; rescued intracellular Trx system
↓ALT and AST levels;↓the serum LN, HA and HYP levels; ↑GPx levels; ↓MDA levels
Hong et al. (123)
CCl4
Male C57BL/6 J mice
↓Collagen I and III, TGF-β, PDGF, CTGF, doublecortin-like kinase, and p-Smad3 expression; ↓MMP-9 activity; ↑Nrf2 expression
Crespo et al. (75)
Bile-duct ligation
Male Wistar rat
↑SOD and GSH levels; ↓MDA levels; ↓TUNEL-positive cells; ↓α-SMA expression
Aktas et al. (124)
Renal fibrosis
Cadmium chloride
Male C57BL/6 mice
↑SOD, GSH, and CAT activities;↓MDA levels; ↓TNF-α and iNOS expression; ↓caspase-3 and Bax expression; ↑Bcl-2 expression; ↓collagen deposition and fibrosis
Yang et al. (128)
Lactacystin
Male Wistar rat
↓HYP levels; ↓the ratio and total amount of collagen I and III
Repova et al. (129)
TGF-β1
Renal interstitial fibroblast
↓The proliferation and activation of renal interstitial fibroblast;↓ROS and MDA levels; ↑GSH/oxidized GSH ratio; ↓Smad and non-Smad signaling cascades
Kim et al. (130)
Skin fibrosis
Skin fibroblast
↓the migration and contractility of HSF; ↓ collagen and α-SMA production; ↓ PI3K/Akt/mTOR signaling
Dong et al. (134)
Wound on ventral surface of ear
Male New Zealand white rabbit
Keloid fibroblast
↑c-PARP, c-caspase3 and c-caspase9 expression; ↓cell proliferation, migration and invasion, contractile capability and collagen production; ↓the Erk and Smad pathways
Cardiac fibrosis is the ultimate pathological outcome of various cardiovascular diseases, commonly seen in myocardial infarction (MI), hypertension, myocarditis, cardiomyopathy, arrhythmias, diabetes and radiation exposure (97). Its main pathological features include excessive proliferation of cardiac fibroblasts and ECM protein deposition, leading to progressive diastolic and systolic dysfunction, which eventually results in chronic heart failure, and sudden cardiac arrest (98, 99). Numerous studies have shown that melatonin affects the cardiovascular system. In cardiovascular diseases, levels of melatonin are found to be reduced (100–102). Melatonin therapy can effectively alleviate fibrosis following these diseases. Melatonin can mitigate cardiac dysfunction and fibrosis induced by fine particulate matter (PM2.5) in mice by inhibiting the phenotypic transformation of cardiac fibroblasts into myofibroblasts. This mechanism may involve the suppression of mitochondrial oxidative damage and regulation of sirtuins 3 (SIRT3)-mediated SOD2 deacetylation (103). MiR-141 is an upstream factor in cardiac fibrosis, involved in regulating NLRP3 and TGF-β1. Melatonin can improve cardiac function and reduce collagen production in diabetic mice by inhibiting the lncR-MALAT1/miR-141 mediated activation of the NLRP3 inflammasome and TGF-β1/Smads signaling pathway (104).Histone deacetylases (HDAC) are involved in several processes related to cardiovascular diseases, including cardiac hypertrophy, remodeling, and fibrosis (105). Melatonin treatment can exert anti-fibrotic effects by inhibiting HDAC expression (106). Additionally, melatonin treatment can alleviate cardiac injury and fibrosis in diabetic mice following MI by inhibiting the JNK/p53-mediated apoptotic pathway. This inhibition reduces the levels of p53, caspase-3, and Bax, while increasing the level of Bcl-2 (107). It is well known that Notch1 plays a significant role in cardiac injury repair (108), and melatonin enhances Notch1/Hes1/Akt signaling in a receptor-dependent manner, rescuing the intracellular thioredoxin (Trx) system, reducing infarct size, cardiomyocyte apoptosis, and oxidative stress, thereby improving myocardial ischemia–reperfusion injury (109).
Melatonin and pulmonary fibrosis
Pulmonary fibrosis is an end-stage lung condition caused by various factors, characterized by fibroblast proliferation and extensive ECM deposition, leading to the destruction of lung tissue structure (110). Pulmonary fibrosis is a major clinical outcome of most chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), radiation and those caused by environmental exposures [e.g., inorganic mineral dust, carbon tetrachloride (CCl4), and bleomycin]. Numerous studies have shown that melatonin can alleviate pulmonary fibrosis caused by various factors. In bleomycin-induced pulmonary fibrosis, melatonin reduces the infiltration and accumulation of inflammatory cells in the alveolar walls (111), as well as the expression of inflammatory mediators such as cyclooxygenase 2 (COX-2) (78). Additionally, melatonin inhibits the increase in hydroxyproline content and the decrease in CAT activity in lung tissue, preventing fibrosis progression by suppressing protein and lipid peroxidation reactions (112). As a key protective regulator in lung diseases, research has found that melatonin also increases the expression of Apelin 13 and inhibits the production of ROS, thereby restoring mitochondrial function and reducing cell apoptosis and senescence during lung injury (113). Melatonin can also effectively inhibit LPS-induced EMT in human type II alveolar epithelial cells (AECs II) by activating the PI3K/Akt signaling pathway, leading to glycogen synthase kinase 3β (GSK-3β) phosphorylation and Nrf2 protein upregulation (114).Furthermore, the Wnt/β-catenin pathway may be involved in various pathological processes of IPF, such as inducing EMT in damaged AECs II and fibrotic cell migration (115, 116). Melatonin inhibits TGF-β1-induced EMT in alveolar epithelial cells by downregulating the Wnt/β-catenin and Smad signaling pathways (117).
Melatonin and hepatic fibrosis
Hepatic fibrosis is a pathological process resulting from liver damage and inflammatory responses caused by various factors such as chronic viral infection, excessive alcohol consumption, exposure to toxic substances, biliary diseases, autoimmune hepatitis (AIH), and non-alcoholic steatohepatitis (NASH). This leads to the activation of hepatic stellate cells (HSCs) and excessive ECM deposition (118). Continued progression of liver fibrosis results in severe complications such as cirrhosis and liver cancer and commonly needs liver transplantation (119).
Numerous in vivo and in vitro experiments have demonstrated that melatonin treatment has a significant effect on alleviating liver fibrosis (120).As the key effector cells in the process of liver fibrosis, HSCs can be activated under conditions of inflammation and oxidative stress, leading to excessive proliferation and transdifferentiation into myofibroblasts. These myofibroblasts express large amounts of α-SMA and ECM proteins, promoting liver fibrosis (121). Melatonin not only reversed the PM2.5-induced increase in MDA and ROS levels and the decrease in GSH levels by activating Nrf2 but also reduced the expression levels of inflammatory factors such as IL-1β, TNF-α, NF-κB, and NLRP3, thereby improving liver function and inhibiting HSCs activation to exert anti-fibrotic effects (122). Melatonin can increase GPx activity and reduce serum markers of liver fibrosis, including hyaluronic acid (HA), hydroxyproline (HYP), and laminin (LN), thereby alleviating CCl4-induced liver dysfunction and fibrosis in rats (123).Additionally, melatonin reduces the expression of collagen I and III, TGF-β, PDGF, CTGF, doublecortin-like kinase, and phosphorylated Smad3, as well as MMP-9 activity, while increasing Nrf2 expression. By limiting multiple pro-fibrotic gene pathways, melatonin alleviates CCl4-induced liver fibrosis in mice (75). In bile duct-ligated rats, melatonin exerts antioxidant effects by increasing SOD and GSH activities, while also reducing hepatocyte apoptosis, thereby alleviating cholestatic liver injury, bile duct proliferation, and fibrosis (124).
Melatonin and renal fibrosis
Renal fibrosis is caused by damage to intrinsic cells (e.g., glomerular podocytes, endothelial cells, mesangial cells, and proximal tubule epithelial cells) due to various pathogenic factors such as ischemia, infection, obstruction, autoimmune diseases, drug injury, hypertension, and diabetes. This damage progresses to extensive collagen deposition and accumulation, leading to the gradual hardening of the renal parenchyma, scar formation, and eventually the complete loss of kidney function (125). It is estimated that chronic kidney disease (CKD) affects 13% of the global population, imposing a significant economic burden on society (126). Renal fibrosis is a common progressive and irreversible pathological feature of CKD, characterized by glomerulosclerosis, tubular atrophy, chronic interstitial inflammation and fibrosis, and vascular rarefaction (127). Currently, there are no effective treatments for renal fibrosis. Research indicates that melatonin can exert antioxidant effects by increasing the activities of SOD, GSH, and CAT and reducing MDA levels in damaged renal tissue. It also exerts anti-inflammatory effects by decreasing the expression of TNF-α and inducible NOS (iNOS), and anti-apoptotic effects by downregulating the expression of caspase-3 and Bax and upregulating the expression of Bcl-2. Consequently, melatonin inhibits the expression of fibrosis-related genes and improves renal damage caused by cadmium exposure in mice (128). Melatonin significantly reduced hydroxyproline levels and the ratio and total amount of collagen I and III in the glomeruli and tubular interstitium in rat with lactoferrin-induced renal fibrosis (129). Additionally, melatonin can inhibit ROS in a receptor-independent manner by suppressing both Smad and non-Smad signaling cascades. This prevents the TGF-β1-induced transdifferentiation of renal interstitial fibroblasts into myofibroblasts, thereby alleviating renal fibrosis (130).
Melatonin and skin fibrosis
Skin fibrosis is characterized by the excessive proliferation of fibroblasts and the deposition of excessive ECM in the dermis, with abnormal cross-linking types, leading to skin hardening and damage (131). Progressive fibrosis mediated by myofibroblasts can invade the skin, causing skin fibrotic diseases, including hypertrophic scar (HS), keloids, localized scleroderma (LS), and systemic sclerosis (SSc), chronic graft-versus-host disease (GVHD) (132). The global impact of skin fibrosis is significant, affecting over 100 million people annually in developed countries (133). Research has found that melatonin enhances autophagy by inhibiting PI3K/Akt/mTOR signaling through the MT2 receptor, thereby inhibiting the migration and contractility of HS fibroblasts (HSFs), as well as the production of collagen and α-SMA, thus playing a role in the prevention and treatment of HS (134).Furthermore, melatonin promotes the apoptosis of keloid fibroblasts (KFs) through the Erk and Smad signaling pathways, inhibiting their proliferation, migration, invasion, contractility, and collagen production, thereby altering the cellular functions of KFs (135).
Clinical applications of melatonin
Dysfunction of melatonin can lead to a range of health issues, including sleep disorders, depression, and decreased immune function (136–138). This, in turn, may increase the risk of developing various conditions such as obesity, diabetes, cardiovascular diseases, and even cancer (139–141). Oral administration of melatonin follows first-order kinetics with a relatively low bioavailability of approximately 15%, which exhibits significant inter-individual variability (142, 143). Melatonin is primarily metabolized in the liver, where it is first hydroxylated to 6-hydroxymelatonin by cytochrome P450 enzymes CYP1A1 and 1A2 enzymes. The majority of this metabolite is then conjugated with sulfate, while a smaller portion is conjugated with glucuronic acid, ultimately being excreted in the urine (144). The absorption half-life is about 6 min, with serum peak concentrations reached on average 40.8 min post-administration, where the maximum concentration can reach 3550.5 pg./mL, thousands of times higher than physiological nighttime levels (125). The average elimination half-life is approximately 53.7 min (125). The low bioavailability and short half-life of melatonin pose significant challenges for its clinical application. Currently, there are melatonin-related compounds, including remelteon, being developed that can last up to 6 h (145).
The incidence of adverse reactions to melatonin is low and its effects are generally mild. Studies have shown positive effects at doses ranging from 2 to 500 mg/day, without any toxic effects (146); even doses of 100 mg/day sustained over a month have shown no substantial negative impact (147). Additionally, administration via various routes has proven to be safe (147).
While there are currently no approved melatonin or derived products for the treatment of fibrotic diseases, numerous cell and animal studies, as mentioned earlier, suggest that melatonin may have potential benefits in managing such conditions. Based on this, a few relevant clinical trials have also been initiated to clarify melatonin’s potential positive influences on fibrotic diseases. For instance, a daily supplementation of 3 mg of melatonin effectively enhanced pulmonary rehabilitation in patients with COPD (148). Similarly, in hypertensive patients, continuous use of a 1 mg/day melatonin supplement for one year effectively improved arterial stiffness (149). However, there are also reports from clinical trials that yielded contrary results. For example, administering melatonin via coronary and intravenous routes did not improve myocardial salvage index in patients with ST-segment elevation myocardial infarction (150). The timing of melatonin usage, the route of administration, and the treatment duration seem to contribute to these conflicting results. Further clinical research is needed to establish the dose–response relationship of melatonin across different diseases and to elucidate the primary mechanisms by which melatonin exerts its effects in these conditions.
Conclusion
Melatonin, as a natural neuroendocrine hormone, has good biocompatibility and safety. This review summarizes the latest advances in melatonin research and treatment for fibrosis. Increasing experimental data indicate that melatonin exerts potential antifibrotic effects in multiple tissues and organs, including the heart, lungs, liver, kidneys, and skin. Its mechanisms of action may involve reducing oxidative stress, inhibiting inflammatory responses, ECM remodeling, suppressing EMT, and regulation of apoptosis. We have identified several common molecular signaling pathways involving melatonin in fibrosis across different organs. The TGF-β pathway is crucial in nearly all types of fibrosis, as it not only has complex regulatory effects on fibrotic effector cells but also interacts with other cellular signaling pathways (97). Additionally, the NF-κB transcription factor family, as a key player in the inflammatory process, plays an important role in fibrosis across different organs (151, 152). Furthermore, the activation of the PI3K/Akt signaling pathway also contributes to the activation of various cytokines involved in fibrosis in different organs (153). Melatonin may inhibit the fibrotic process by regulating these pathways. However, the antifibrotic effects of melatonin are mostly derived from animal studies and fibrotic cell models, lacking clinical trial evidence. Despite some current research limitations, melatonin remains a promising therapeutic target with broad application prospects. Future studies should further elucidate its mechanisms of action in different organ fibrosis and develop corresponding therapeutic strategies, providing new insights and methods for treating fibrotic diseases.
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key Research and Development Program of China (No. 2022YFC2304800) and 1.3.5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (ZYJC21014).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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ReferencesRosenbloomJCastroSVJimenezSA. Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med. (2010) 152:159–66. doi: 10.7326/0003-4819-152-3-201002020-00007RockeyDCBellPDHillJA. Fibrosis--A common pathway to organ injury and failure. N Engl J Med. (2015) 373:96. doi: 10.1056/NEJMc1504848, PMID: 26132959WynnT. Cellular and molecular mechanisms of fibrosis. J Pathol. (2008) 214:199–210. doi: 10.1002/path.2277, PMID: 18161745EspositoECuzzocreaS. Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol. (2010) 8:228–42. doi: 10.2174/157015910792246155, PMID: 21358973LernerABCaseJDTakahashiYLeeTHMoriW. Isolation of melatonin, the pineal gland factor that lightens MELANOCYTES1. J Am Chem Soc. (1958) 80:2587–7. doi: 10.1021/ja01543a060AmaralFGDCipolla-NetoJ. A brief review about melatonin, a pineal hormone. Arch Endocrinol Metab. (2018) 62:472–9. doi: 10.20945/2359-3997000000066, PMID: 30304113GormanMR. Temporal organization of pineal melatonin signaling in mammals. Mol Cell Endocrinol. (2020) 503:110687. doi: 10.1016/j.mce.2019.110687, PMID: 31866317HajakGRodenbeckAStaedtJHuetherGRütherERütherE. Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia. J Pineal Res. (1995) 19:116–22. doi: 10.1111/j.1600-079X.1995.tb00179.x, PMID: 8750344Fernández-DuránBRuibalCPolakofSCeinosRMSoengasJLMíguezJM. Evidence for arylalkylamine N-acetyltransferase (AANAT2) expression in rainbow trout peripheral tissues with emphasis in the gastrointestinal tract. Gen Comp Endocrinol. (2007) 152:289–94. doi: 10.1016/j.ygcen.2006.12.008, PMID: 17292900BuxtonOML'Hermite-BalériauxMHirschfeldUvan CauterE. Acute and delayed effects of exercise on human melatonin secretion. J Biol Rhythm. (1997) 12:568–74. doi: 10.1177/074873049701200611, PMID: 9406031CassoneVM. Effects of melatonin on vertebrate circadian systems. Trends Neurosci. (1990) 13:457–64. doi: 10.1016/0166-2236(90)90099-VReppertSMWeaverDREbisawaT. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. (1994) 13:1177–85. doi: 10.1016/0896-6273(94)90055-8, PMID: 7946354ReppertSMGodsonCMahleCDWeaverDRSlaugenhauptSAGusellaJF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci. (1995) 92:8734–8. doi: 10.1073/pnas.92.19.8734NosjeanOFerroMCogéFBeauvergerPHenlinJMLefoulonF. Identification of the melatonin-binding SiteMT 3 as the Quinone reductase 2*. J Biol Chem. (2000) 275:31311–7. doi: 10.1074/jbc.M005141200, PMID: 10913150LuoCYangQLiuYZhouSJiangJReiterRJ. The multiple protective roles and molecular mechanisms of melatonin and its precursor N-acetylserotonin in targeting brain injury and liver damage and in maintaining bone health. Free Radic Biol Med. (2019) 130:215–33. doi: 10.1016/j.freeradbiomed.2018.10.402AshrafizadehMNajafiMKavyianiNMohammadinejadRFarkhondehTSamarghandianS. Anti-inflammatory activity of melatonin: a focus on the role of NLRP3 Inflammasome. Inflammation. (2021) 44:1207–22. doi: 10.1007/s10753-021-01428-9, PMID: 33651308GurtnerGCWernerSBarrandonYLongakerMT. Wound repair and regeneration. Nature. (2008) 453:314–21. doi: 10.1038/nature07039LiXMoNLiZ. Ginsenosides: potential therapeutic source for fibrosis-associated human diseases. J Ginseng Res. (2020) 44:386–98. doi: 10.1016/j.jgr.2019.12.003, PMID: 32372860WynnTAVannellaKM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. (2016) 44:450–62. doi: 10.1016/j.immuni.2016.02.015, PMID: 26982353StramerBMMoriRMartinP. The inflammation–fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J Invest Dermatol. (2007) 127:1009–17. doi: 10.1038/sj.jid.5700811HinzBPhanSHThannickalVJGalliABochaton-PiallatMLGabbianiG. The Myofibroblast: one function, multiple origins. Am J Pathol. (2007) 170:1807–16. doi: 10.2353/ajpath.2007.070112, PMID: 17525249KirkTZMarkMEChuaCCChuaBHMayesMD. Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem. (1995) 270:3423–8. doi: 10.1074/jbc.270.7.3423, PMID: 7852429HinzBPhanSHThannickalVJPrunottoMDesmoulièreAVargaJ. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. (2012) 180:1340–55. doi: 10.1016/j.ajpath.2012.02.004, PMID: 22387320McanultyRJ. Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol. (2007) 39:666–71. doi: 10.1016/j.biocel.2006.11.005, PMID: 17196874KarasekMA. Does transformation of microvascular endothelial cells into myofibroblasts play a key role in the etiology and pathology of fibrotic disease?Med Hypotheses. (2007) 68:650–5. doi: 10.1016/j.mehy.2006.07.053Piera-VelazquezSMendozaFAJimenezSA. Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of human fibrotic diseases. J Clin Med. (2016) 5:45. doi: 10.3390/jcm5040045, PMID: 27077889LamouilleSXuJDerynckR. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. (2014) 15:178–96. doi: 10.1038/nrm3758, PMID: 24556840duYMaJFanYWangXZhengSFengJ. Naringenin: A promising therapeutic agent against organ fibrosis. Oxidative Med Cell Longev. (2021) 2021:1210675. doi: 10.1155/2021/1210675, PMID: 34804359LuaIAsahinaK. The role of mesothelial cells in liver development, injury, and regeneration. Gut Liver. (2016) 10:166–76. doi: 10.5009/gnl15226, PMID: 26934883KimKKSheppardDChapmanHA. TGF-β1 signaling and tissue fibrosis. Cold Spring Harb Perspect Biol. (2018) 10:a022293. doi: 10.1101/cshperspect.a022293IsshikiTNaielSVierhoutMOtsuboKAliPTsubouchiK. Therapeutic strategies to target connective tissue growth factor in fibrotic lung diseases. Pharmacol Ther. (2024) 253:108578. doi: 10.1016/j.pharmthera.2023.108578, PMID: 38103794KaschinaELauerDLangeCUngerT. Angiotensin AT(2) receptors reduce inflammation and fibrosis in cardiovascular remodeling. Biochem Pharmacol. (2024) 222:116062. doi: 10.1016/j.bcp.2024.116062, PMID: 38369211ZhangXZhangXHuangWGeX. The role of heat shock proteins in the regulation of fibrotic diseases. Biomed Pharmacother. (2021) 135:111067. doi: 10.1016/j.biopha.2020.111067SwigrisJJBrownKK. The role of endothelin-1 in the pathogenesis of idiopathic pulmonary fibrosis. BioDrugs. (2010) 24:49–54. doi: 10.2165/11319550-000000000-00000, PMID: 20055532LiRFrangogiannisNG. Integrins in cardiac fibrosis. J Mol Cell Cardiol. (2022) 172:1–13. doi: 10.1016/j.yjmcc.2022.07.006MorikawaMDerynckRMiyazonoKJCSHPIB. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Perspect Biol. (2016) 8:a021873. doi: 10.1101/cshperspect.a021873, PMID: 27141051OngCHThamCLHarithHHFirdausNIsrafDA. TGF-β-induced fibrosis: A review on the underlying mechanism and potential therapeutic strategies. Eur J Pharmacol. (2021) 911:174510. doi: 10.1016/j.ejphar.2021.174510, PMID: 34560077KamatoDBurchMLPivaTJRezaeiHBRostamMAXuS. Transforming growth factor-β signalling: role and consequences of Smad linker region phosphorylation. Cell Signal. (2013) 25:2017–24. doi: 10.1016/j.cellsig.2013.06.001, PMID: 23770288HuHHChenDQWangYNFengYLCaoGVaziriND. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. (2018) 292:76–83. doi: 10.1016/j.cbi.2018.07.008, PMID: 30017632HeldinCHMoustakasA. Signaling receptors for TGF-β family members. Cold Spring Harb Perspect Biol. (2016) 8:a022053. doi: 10.1101/cshperspect.a022053PalumboKZerrPTomcikMDeesCAkhmetshinaAAvouacJ. The transcription factor JunD mediates transforming growth factor -induced fibroblast activation and fibrosis in systemic sclerosis. Ann Rheum Dis. (2011) 70:1320–6. doi: 10.1136/ard.2010.148296, PMID: 21515915WangY-LZhaoX-MShuaiZ-FLiCYBaiQYYuXW. Snail promotes epithelial-mesenchymal transition and invasiveness in human ovarian cancer cells. Int J Clin Exp Med. (2015) 8:7388.ChangYCTsaiCHLaiYLYuCCChiWYLiJJ. Arecoline‐induced myofibroblast transdifferentiation from human buccal mucosal fibroblasts is mediated byZEB1. J Med Biochem. (2014) 18:698–708. doi: 10.1111/jcmm.12219, PMID: 24400868WhiteSLinLHuK. NF-κB and tPA signaling in kidney and other diseases. Cells. (2020) 9:1348. doi: 10.3390/cells9061348, PMID: 32485860JaffarJGlaspoleISymonsKWestallG. Inhibition of NF-κB by ACT001 reduces fibroblast activity in idiopathic pulmonary fibrosis. Biomed Pharmacother. (2021) 138:111471. doi: 10.1016/j.biopha.2021.111471, PMID: 33730605BrzezinskiA. Melatonin in humans. N Engl J Med. (1997) 336:186–95. doi: 10.1056/NEJM199701163360306ArmstrongSM. Melatonin and circadian control in mammals. Experientia. (1989) 45:932–8. doi: 10.1007/BF01953050JungBAhmadN. Melatonin in cancer management: progress and promise. Cancer Res. (2006) 66:9789–93. doi: 10.1158/0008-5472.CAN-06-1776, PMID: 17047036SzczepanikM. Melatonin and its influence on immune system. J Physiol Pharmacol. (2007) 58:115–24. doi: 10.2170/physiolsci.SC008107ReiterRJTanDXGittoESainzRMMayoJCLeonJ. Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Pol J Pharmacol. (2004) 56:159–70. PMID: 15156066KozinaLSArutjunyanAVKhavinsonVK. Antioxidant properties of geroprotective peptides of the pineal gland. Arch Gerontol Geriatr. (2007) 44:213–6. doi: 10.1016/j.archger.2007.01.029, PMID: 17317455TengattiniSReiterRJTanD-XTerronMPRodellaLFRezzaniR. Cardiovascular diseases: protective effects of melatonin. J Pineal Res. (2008) 44:16–25. doi: 10.1111/j.1600-079X.2007.00518.xUrtasunRConde De La RosaLNietoN. Oxidative and nitrosative stress and fibrogenic response. Clin Liver Dis. (2008) 12:769–790, viii. doi: 10.1016/j.cld.2008.07.005, PMID: 18984466LeiXXuZHuangLHuangYTuSXuL. The potential influence of melatonin on mitochondrial quality control: a review. Front Pharmacol. (2023) 14:1332567. doi: 10.3389/fphar.2023.1332567LiDPanJHHuangXFLiaoYQLingYJLuoJY. Effect of melatonin on oxidative stress indicators in animal models of fibrosis: A systematic review and meta-analysis. Free Radic Biol Med. (2023) 195:158–77. doi: 10.1016/j.freeradbiomed.2022.12.094, PMID: 36586451LimsonJNyokongTDayaS. The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study. J Pineal Res. (1998) 24:15–21. doi: 10.1111/j.1600-079X.1998.tb00361.x, PMID: 9468114ReiterRJMayoJCTanD-XSainzRMAlatorre-JimenezMQinL. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. (2016) 61:253–78. doi: 10.1111/jpi.12360, PMID: 27500468PaskaloğluKŞenerGKapucuCAyanoğlu-DülgerG. Melatonin treatment protects against sepsis-induced functional and biochemical changes in rat ileum and urinary bladder. Life Sci. (2004) 74:1093–104. doi: 10.1016/j.lfs.2003.07.038, PMID: 14687650SenerGTokluHKapucuCErcanFErkanliGKaçmazA. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surg Today. (2005) 35:52–9. doi: 10.1007/s00595-004-2879-1, PMID: 15622465FjaerliOLundTOsterudB. The effect of melatonin on cellular activation processes in human blood. J Pineal Res. (1999) 26:50–5. doi: 10.1111/j.1600-079X.1999.tb00566.x, PMID: 10102760SilvaSORodriguesMRXimenesVFBueno-da-SilvaAEBAmarante-MendesGPCampaA. Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release. J Neuroimmunol. (2004) 156:146–52. doi: 10.1016/j.jneuroim.2004.07.015, PMID: 15465605LiuSCTsaiCHWangYHSuCMWuHCFongYC. Melatonin abolished proinflammatory factor expression and antagonized osteoarthritis progression in vivo. Cell Death Dis. (2022) 13:215. doi: 10.1038/s41419-022-04656-5, PMID: 35256585NegiGKumarASharmaSS. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-κB and Nrf2 cascades. J Pineal Res. (2011) 50:124–31. doi: 10.1111/j.1600-079X.2010.00821.x, PMID: 21062351IsmailIAEl-BakryHASolimanSS. Melatonin and tumeric ameliorate aging-induced changes: implication of immunoglobulins, cytokines, DJ-1/NRF2 and apoptosis regulation. Int J Physiol Pathophysiol Pharmacol. (2018) 10:70–82. PMID: 29755640HardelandR. Melatonin and inflammation—story of a double-edged blade. J Pineal Res. (2018) 65:e12525. doi: 10.1111/jpi.12525, PMID: 30242884BiliciDAkpinarEKiziltunçA. Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharmacol Res. (2002) 46:133–9. doi: 10.1016/S1043-6618(02)00089-0, PMID: 12220952SuS-CHsiehM-JYangW-EChungWHReiterRJYangSF. Cancer metastasis: mechanisms of inhibition by melatonin. J Pineal Res. (2017) 62:e12370. doi: 10.1111/jpi.12370JunJ-ILauLFJTJOCI. Resolution of organ fibrosis. Clin Res. (2018) 128:97–107. doi: 10.1172/JCI93563, PMID: 29293097GillSEParksWC. Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol. (2008) 40:1334–47. doi: 10.1016/j.biocel.2007.10.024, PMID: 18083622ParksWCWilsonCLLópez-BoadoYSJNRI. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immun. (2004) 4:617–29. doi: 10.1038/nri1418, PMID: 15286728ButlerGSOverallCMJP. Matrix metalloproteinase processing of signaling molecules to regulate inflammation. Periodontol. (2013) 63:123–48. doi: 10.1111/prd.12035SwarnakarSPaulSSinghLPReiterRJ. Matrix metalloproteinases in health and disease: regulation by melatonin. J Pineal Res. (2011) 50:8–20. doi: 10.1111/j.1600-079X.2010.00812.x, PMID: 20964709RudraDSPalUMaitiNCReiterRJSwarnakarS. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res. (2013) 54:398–405. doi: 10.1111/jpi.12034, PMID: 23330737KapoorCVaidyaSWadhwanVHiteshKaurGPathakA. Seesaw of matrix metalloproteinases (MMPs). J Cancer Res Ther. (2016) 12:28–35. doi: 10.4103/0973-1482.157337, PMID: 27072206CrespoISan-MiguelBFernándezAOrtiz de UrbinaJGonzález-GallegoJTuñónMJ. Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice. Transl Res. (2015) 165:346–57. doi: 10.1016/j.trsl.2014.10.003, PMID: 25445210SimkoFPechanovaOPelouchVKrajcirovicovaKMullerovaMBednarovaK. Effect of melatonin, captopril, spironolactone and simvastatin on blood pressure and left ventricular remodelling in spontaneously hypertensive rats. J Hypertens Suppl. (2009) 27:S5–S10. doi: 10.1097/01.hjh.0000358830.95439.e8MarquezESánchez-FidalgoSCalvoJRLastraCAMotilvaV. Acutely administered melatonin is beneficial while chronic melatonin treatment aggravates the evolution of TNBS-induced colitis. J Pineal Res. (2006) 40:48–55. doi: 10.1111/j.1600-079X.2005.00275.x, PMID: 16313498KarimfarMHRostamiSHaghaniKBakhtiyariSNoori-ZadehA. Melatonin alleviates bleomycin-induced pulmonary fibrosis in mice. J Biol Regul Homeost Agents. (2015) 29:327–34. PMID: 26122220DrobnikJSlotwinskaDOlczakSTosikDPieniazekAMatczakK. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. (2011) 62:29–35. PMID: 21451207ShookDKellerR. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. (2003) 120:1351–83. doi: 10.1016/j.mod.2003.06.005, PMID: 14623443HeerbothSHousmanGLearyMLongacreMBylerSLapinskaK. EMT and tumor metastasis. Clin Transl Med. (2015) 4:6. doi: 10.1186/s40169-015-0048-3LovisaSLeBleuVSTampeBSugimotoHVadnagaraKCarstensJL. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. (2015) 21:998–1009. doi: 10.1038/nm.3902, PMID: 26236991YoussefKKNietoMA. Epithelial-mesenchymal transition in tissue repair and degeneration. Nat Rev Mol Cell Biol. (2024) 25:720–39. doi: 10.1038/s41580-024-00733-z, PMID: 38684869López-NovoaJMNietoMA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. (2009) 1:303–14. doi: 10.1002/emmm.200900043, PMID: 20049734QiSYanLLiuZMuYLLiMZhaoX. Melatonin inhibits 17β-estradiol-induced migration, invasion and epithelial-mesenchymal transition in normal and endometriotic endometrial epithelial cells. Reprod Biol Endocrinol. (2018) 16:62. doi: 10.1186/s12958-018-0375-5, PMID: 29935526QinTFengDZhouBBaiLYinY. Melatonin suppresses LPS-induced oxidative stress in dendritic cells for inflammatory regulation via the Nrf2/HO-1 Axis. Antioxidants (Basel). (2022) 11:2012. doi: 10.3390/antiox11102012ShiSZhangYWenWZhaoYSunL. Molecular mechanisms of melatonin in the reversal of LPS-induced EMT in peritoneal mesothelial cells. Mol Med Rep. (2016) 14:4342–8. doi: 10.3892/mmr.2016.5744, PMID: 27634300HettsSW. To die or not to die: an overview of apoptosis and its role in disease. JAMA. (1998) 279:300–7. doi: 10.1001/jama.279.4.300JanRChaudhryGE. Understanding apoptosis and apoptotic pathways targeted Cancer therapeutics. Adv Pharm Bull. (2019) 9:205–18. doi: 10.15171/apb.2019.024, PMID: 31380246KimR. Recent advances in understanding the cell death pathways activated by anticancer therapy. Cancer. (2005) 103:1551–60. doi: 10.1002/cncr.20947JinZEl-DeiryWS. Overview of cell death signaling pathways. Cancer Biol Ther. (2005) 4:139–63. doi: 10.4161/cbt.4.2.1508, PMID: 15725726KumarRHerbertPEWarrensAN. An introduction to death receptors in apoptosis. Int J Surg. (2005) 3:268–77. doi: 10.1016/j.ijsu.2005.05.002KimJWJoJKimJYChoeMLeemJParkJH. Melatonin attenuates cisplatin-induced acute kidney injury through dual suppression of apoptosis and necroptosis. Biology (Basel). (2019) 8:64. doi: 10.3390/biology8030064HoijmanERocha ViegasLKeller SarmientoMIRosensteinREPecciA. Involvement of Bax protein in the prevention of glucocorticoid-induced thymocytes apoptosis by melatonin. Endocrinology. (2004) 145:418–25. doi: 10.1210/en.2003-0764, PMID: 14500572XieYFZhangJCLiuSJDaiLBduGW. Effect of melatonin on proliferation and apoptosis of fibroblasts in human hypertrophic scar. Zhonghua Shao Shang Za Zhi. (2011) 27:422–6. doi: 10.3760/cma.j.issn.1009-2587.2011.06.005 PMID: 22340787Ben SoussiaIMiesFNaeijeRShlyonskyV. Melatonin down-regulates volume-sensitive chloride channels in fibroblasts. Pflugers Arch. (2012) 464:273–85. doi: 10.1007/s00424-012-1139-2, PMID: 22837012RockeyDCBellPDHillJA. Fibrosis — A common pathway to organ injury and failure. N Engl J Med. (2015) 372:1138–49. doi: 10.1056/NEJMra1300575BerkBCFujiwaraKLehouxS. ECM remodeling in hypertensive heart disease. J Clin Invest. (2007) 117:568–75. doi: 10.1172/JCI31044, PMID: 17332884NguyenTPQuZWeissJN. Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils. J Mol Cell Cardiol. (2014) 70:83–91. doi: 10.1016/j.yjmcc.2013.10.018, PMID: 24184999MisakaTYoshihisaAYokokawaTSatoTOikawaMKobayashiA. Plasma levels of melatonin in dilated cardiomyopathy. J Pineal Res. (2019) 66:e12564. doi: 10.1111/jpi.12564, PMID: 30715754LusardiPPiazzaEFogariR. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol. (2000) 49:423–7. doi: 10.1046/j.1365-2125.2000.00195.x, PMID: 10792199Dominguez-RodriguezAAbreu-GonzalezPArroyo-UcarEReiterRJ. Decreased level of melatonin in serum predicts left ventricular remodelling after acute myocardial infarction. J Pineal Res. (2012) 53:319–23. doi: 10.1111/j.1600-079X.2012.01001.x, PMID: 22537272JiangJLiangSZhangJduZXuQDuanJ. Melatonin ameliorates PM(2.5) -induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis. J Pineal Res. (2021) 70:e12686. doi: 10.1111/jpi.12686, PMID: 32730639CheHWangYLiHLiYSahilALvJ. Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR-141-mediated NLRP3 inflammasome and TGF-β1/Smads signaling in diabetic cardiomyopathy. FASEB J. (2020) 34:5282–98. doi: 10.1096/fj.201902692R, PMID: 32067273BagchiRAWeeksKL. Histone deacetylases in cardiovascular and metabolic diseases. J Mol Cell Cardiol. (2019) 130:151–9. doi: 10.1016/j.yjmcc.2019.04.003WuYSiFLuoLJingFJiangKZhouJ. The effect of melatonin on cardio fibrosis in juvenile rats with pressure overload and deregulation of HDACs. Korean J Physiol Pharmacol. (2018) 22:607–16. doi: 10.4196/kjpp.2018.22.6.607, PMID: 30402021LuLMaJSunMWangXGaoELuL. Melatonin ameliorates MI-induced cardiac remodeling and apoptosis through a JNK/p53-dependent mechanism in diabetes mellitus. Oxidative Med Cell Longev. (2020) 2020:1–14. doi: 10.1155/2020/1535201LiYHiroiYLiaoJK. Notch signaling as an important mediator of cardiac repair and regeneration after myocardial infarction. Trends Cardiovasc Med. (2010) 20:228–31. doi: 10.1016/j.tcm.2011.11.006, PMID: 22293023YuLFanCLiZZhangJXueXXuY. Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. J Pineal Res. (2017) 62:1–17. doi: 10.1111/jpi.12375, PMID: 27753144WuytsWAAgostiniCAntoniouKMBourosDChambersRCCottinV. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. (2013) 41:1207–18. doi: 10.1183/09031936.00073012, PMID: 23100500GenoveseTPaolaRDMazzonEMuiàCCaputiAPCuzzocreaS. Melatonin limits lung injury in bleomycin treated mice. J Pineal Res. (2005) 39:105–12. doi: 10.1111/j.1600-079X.2005.00229.x, PMID: 16098086YildirimZKotukMErdoganHIrazMYagmurcaMKukuI. Preventive effect of melatonin on bleomycin-induced lung fibrosis in rats. J Pineal Res. (2006) 40:27–33. doi: 10.1111/j.1600-079X.2005.00272.x, PMID: 16313495ZhangLLiFSuXLiYWangYFangR. Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction. Exp Mol Med. (2019) 51:1–12. doi: 10.1038/s12276-019-0273-8, PMID: 31273199DingZWuXWangYJiSZhangWKangJ. Melatonin prevents LPS-induced epithelial-mesenchymal transition in human alveolar epithelial cells via the GSK-3β/Nrf2 pathway. Biomed Pharmacother. (2020) 132:110827. doi: 10.1016/j.biopha.2020.110827HendersonWRChiEYYeXNguyenCTienYTZhouB. Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. PNAS Nexus. (2010) 107:14309–14. doi: 10.1073/pnas.1001520107, PMID: 20660310LamAPGottardiCJ. β-Catenin signaling: a novel mediator of fibrosis and potential therapeutic target. Curr Opin Rheumatol. (2011) 23:562–7. doi: 10.1097/BOR.0b013e32834b3309, PMID: 21885974YuNSunYTSuXMHeMDaiBKangJ. Melatonin attenuates TGFβ1-induced epithelial-mesenchymal transition in lung alveolar epithelial cells. Mol Med Rep. (2016) 14:5567–72. doi: 10.3892/mmr.2016.5950, PMID: 27878256GinèsPCárdenasAArroyoVRodésJ. Management of cirrhosis and ascites. N Engl J Med. (2004) 350:1646–54. doi: 10.1056/NEJMra035021BatallerRBrennerDA. Liver fibrosis. J Clin Invest. (2005) 115:209–18. doi: 10.1172/JCI24282, PMID: 15690074HosseinzadehAPourhanifehMHAmiriSSheibaniMIrilouzadianRReiterRJ. Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis. Pharmacol Rep. (2024) 76:25–50. doi: 10.1007/s43440-023-00554-5ElpekG. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J Gastroenterol. (2014) 20:7260–76. doi: 10.3748/wjg.v20.i23.7260, PMID: 24966597ZhuLZhangQHuaCCiX. Melatonin alleviates particulate matter-induced liver fibrosis by inhibiting ROS-mediated mitophagy and inflammation via Nrf2 activation. Ecotoxicol Environ Saf. (2023) 268:115717. doi: 10.1016/j.ecoenv.2023.115717, PMID: 37992643HongRTXuJMMeiQ. Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats. World J Gastroenterol. (2009) 15:1452–8. doi: 10.3748/wjg.15.1452, PMID: 19322917AktasCKanterMErbogaMMeteROranM. Melatonin attenuates oxidative stress, liver damage and hepatocyte apoptosis after bile-duct ligation in rats. Toxicol Ind Health. (2014) 30:835–44. doi: 10.1177/0748233712464811, PMID: 23095487TampeDZeisbergM. Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol. (2014) 10:226–37. doi: 10.1038/nrneph.2014.14AmmiratiAL. Chronic kidney disease. Rev Assoc Med Bras. (2020) 66:s03–9. doi: 10.1590/1806-9282.66.s1.3DjudjajSBoorP. Cellular and molecular mechanisms of kidney fibrosis. Mol Asp Med. (2019) 65:16–36. doi: 10.1016/j.mam.2018.06.002YangZHeYMaQWangHZhangQ. Alleviative effect of melatonin against the nephrotoxicity induced by cadmium exposure through regulating renal oxidative stress, inflammatory reaction, and fibrosis in a mouse model. Ecotoxicol Environ Saf. (2023) 265:115536. doi: 10.1016/j.ecoenv.2023.115536, PMID: 37797427RepovaKStankoPBakaTKrajcirovicovaKAziriovaSHrenakJ. Lactacystin-induced kidney fibrosis: protection by melatonin and captopril. Front Pharmacol. (2022) 13:978337. doi: 10.3389/fphar.2022.978337, PMID: 36176443KimJYParkJHJeonEJLeemJParkKK. Melatonin prevents transforming growth factor-β1-stimulated Transdifferentiation of renal interstitial fibroblasts to Myofibroblasts by suppressing reactive oxygen species-dependent mechanisms. Antioxidants (Basel). (2020) 9:39. doi: 10.3390/antiox9010039NguyenJKAustinEHuangAMamalisAJagdeoJ. The IL-4/IL-13 axis in skin fibrosis and scarring: mechanistic concepts and therapeutic targets. Arch Dermatol Res. (2020) 312:81–92. doi: 10.1007/s00403-019-01972-3, PMID: 31493000GriffinMFDesjardins-ParkHEMascharakSBorrelliMRLongakerMT. Understanding the impact of fibroblast heterogeneity on skin fibrosis. Dis Model Mech. (2020) 13:dmm044164. doi: 10.1242/dmm.044164, PMID: 32541065BayatAMcgroutherDAFergusonMW. Skin scarring. BMJ. (2003) 326:88–92. doi: 10.1136/bmj.326.7380.88, PMID: 12521975DongYCaoXHuangJHuZChenCChenM. Melatonin inhibits fibroblast cell functions and hypertrophic scar formation by enhancing autophagy through the MT2 receptor-inhibited PI3K/Akt /mTOR signaling. Biochim Biophys Acta Mol basis Dis. (2024) 1870:166887. doi: 10.1016/j.bbadis.2023.166887, PMID: 37739092HuangSDengWDongYHuZZhangYWangP. Melatonin influences the biological characteristics of keloid fibroblasts through the Erk and Smad signalling pathways. Burns. Trauma. (2023) 11:tkad005. doi: 10.1093/burnst/tkad005ComaiSGobbiG. Melatonin, melatonin receptors and sleep: moving beyond traditional views. J Pineal Res. (2024) 76:e13011. doi: 10.1111/jpi.13011, PMID: 39400423YousefiTYousef MemarMAhmadi JaziAZandSReiterRJAmirkhanlouS. Molecular pathways and biological roles of melatonin and vitamin D; effects on immune system and oxidative stress. Int Immunopharmacol. (2024) 143:113548. doi: 10.1016/j.intimp.2024.113548, PMID: 39488920HeSYuYChenPQSunHMGaoXRSunHZ. Insufficient plasma melatonin and its association with neuropsychiatric impairments in patients with T2DM. J Diabetes Res. (2024) 2024:5661751. doi: 10.1155/2024/5661751, PMID: 38988702ZambranoCGaritaonaindiaMTSalmerónDPérez-SanzFTchioCPicinatoMC. Melatonin decreases human adipose tissue insulin sensitivity. J Pineal Res. (2024) 76:e12965. doi: 10.1111/jpi.12965SongY-JZhongC-BWuW. Cardioprotective effects of melatonin: focusing on its roles against diabetic cardiomyopathy. Biomed Pharmacother. (2020) 128:110260. doi: 10.1016/j.biopha.2020.110260BlaskDEBrainardGCDauchyRTHanifinJPDavidsonLKKrauseJA. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. (2005) 65:11174–84. doi: 10.1158/0008-5472.CAN-05-1945, PMID: 16322268AndersenLPWernerMURosenkildeMMHarpsøeNGFuglsangHRosenbergJ. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers. BMC Pharmacol Toxicol. (2016) 17:8. doi: 10.1186/s40360-016-0052-2HarpsøeNGAndersenLPGögenurIRosenbergJ. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. (2015) 71:901–9. doi: 10.1007/s00228-015-1873-4, PMID: 26008214LuKHLinRCYangJSYangWEReiterRJYangSF. Molecular and cellular mechanisms of melatonin in osteosarcoma. Cells. (2019) 8:1618. doi: 10.3390/cells8121618, PMID: 31842295WilliamsWPMcLinDEIIIDressmanMANeubauerDN. Comparative Review of approved melatonin agonists for the treatment of circadian rhythm sleep-wake disorders. Pharmacotherapy. (2016) 36:1028–41. doi: 10.1002/phar.1822, PMID: 27500861ReiterRJSharmaRSimkoFDominguez-RodriguezATesarikJNeelRL. Melatonin: highlighting its use as a potential treatment for SARS-CoV-2 infection. Cell Mol Life Sci. (2022) 79:143. doi: 10.1007/s00018-021-04102-3, PMID: 35187603NordlundJJLernerAB. The effects of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab. (1977) 45:768–74. doi: 10.1210/jcem-45-4-768, PMID: 914981VianaSde BruinVMSVasconcelosRSNogueiraANCMesquitaRde BruinPFC. Melatonin supplementation enhances pulmonary rehabilitation outcomes in COPD: a randomized, double-blind, placebo-controlled study. Respir Med. (2023) 220:107441. doi: 10.1016/j.rmed.2023.107441, PMID: 37944829FrancoCSciattiEFaveroGBonominiFVizzardiERezzaniR. Essential hypertension and oxidative stress: novel future perspectives. Int J Mol Sci. (2022) 23:14489. doi: 10.3390/ijms232214489, PMID: 36430967EkeloefSHalladinNFonnesSJensenSEZarembaTRosenbergJ. Effect of intracoronary and intravenous melatonin on myocardial salvage index in patients with ST-elevation myocardial infarction: a randomized placebo controlled trial. J Cardiovasc Transl Res. (2017) 10:470–9. doi: 10.1007/s12265-017-9768-7YamamotoYGaynorRB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest. (2001) 107:135–42. doi: 10.1172/JCI11914, PMID: 11160126FranceschettiLBonominiFRodellaLFRezzaniR. Critical role of NFκB in the pathogenesis of non-alcoholic fatty liver disease: A widespread key regulator. Curr Mol Med. (2021) 21:495–505. doi: 10.2174/1566524020666201026162343, PMID: 33106141KimMSRådingerMGilfillanAM. The multiple roles of phosphoinositide 3-kinase in mast cell biology. Trends Immunol. (2008) 29:493–501. doi: 10.1016/j.it.2008.07.004, PMID: 18775670