Melatonin, a pleiotropic indoleamine, plays a crucial role in maintaining redox homeostasis by directly scavenging reactive oxygen species (ROS) and enhancing endogenous antioxidant defenses. Beyond its well-established circadian function, melatonin regulates oxidative stress, inflammation, apoptosis, and autophagy, positioning it as a promising therapeutic candidate in various pathophysiological contexts, including cancer, neurodegenerative disorders, cardiovascular disease, and aging [1, 2].

One of the key processes influenced by melatonin is lipid peroxidation (LP), an oxidative chain reaction triggered by ROS that targets unsaturated fatty acids in cellular membranes, producing reactive aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) [3, 4]. While excessive LP compromises membrane integrity and mitochondrial function, contributing to genomic instability and inflammation, regulated LP can act as a signaling mechanism, modulating adaptive pathways such as apoptosis and ferroptosis [5, 6].

Melatonin exerts protective effects by neutralizing ROS, reducing the formation of cytotoxic aldehydes, and preventing protein and DNA adducts that disrupt cellular homeostasis [7]. Importantly, it not only suppresses harmful LP but also fine-tunes redox-dependent signaling, preserving the physiological functions of lipid-derived mediators. This dual action distinguishes melatonin from traditional antioxidants, which may blunt essential oxidative signaling.

In cancer, where LP has a paradoxical role—promoting both tumor progression and ferroptotic cell death—melatonin emerges as a modulator capable of tipping the balance toward protective outcomes. By restoring redox balance and regulating ferroptosis, melatonin offers a unique therapeutic avenue for oxidative stress–related diseases [8, 9].

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous indoleamine synthesized in a circadian manner in the pineal gland and in a non-circadian manner in many other cells [10]. In the pineal, its secretion is tightly regulated by the suprachiasmatic nucleus and modulated by the light/dark cycle. Peripheral tissues where melatonin synthesis has been documented include the gastrointestinal tract, adrenal cortex, retina, immune cells, and others. The presence of melatonin synthesis in multiple tissues underscores its broad involvement in autocrine and paracrine signaling pathways [11, 12]. More recently, compelling evidence has demonstrated that mitochondria represent the primary intracellular source of melatonin in many tissues [13, 14]. Unlike pineal synthesis, which depends on photoperiod regulation, mitochondrial melatonin production responds directly to metabolic demands, bioenergetic status, and the cellular redox environment, acting as a relevant local defense mechanism, complementary to other antioxidant systems [9, 13, 15].

The biosynthetic pathway of melatonin begins with the essential amino acid tryptophan, which is converted into 5-hydroxytryptophan by the enzyme tryptophan hydroxylase (TPH), followed by decarboxylation into serotonin by aromatic L-amino acid decarboxylase (AADC). The rate-limiting step occurs through the activity of serotonin N-acetyltransferase (SNAT), also known as arylalkylamine N-acetyltransferase (AANAT), which catalyzes the conversion of serotonin into N-acetylserotonin. Subsequently, the enzyme hydroxyindole-O-methyltransferase (HIOMT)—currently designated as acetylserotonin-O-methyltransferase (ASMT)—methylates N-acetylserotonin to produce melatonin [9, 13, 15]. This biosynthesis depends on the availability of serotonin and cofactors such as zinc, an essential element that also participates in antioxidant defense, underscoring that melatonin production is interconnected with broader metabolic and redox pathways.

Although widely recognized for its pivotal role in circadian rhythm regulation, melatonin exerts effects that extend beyond chronobiology. It is a multifunctional molecule that contributes to cellular homeostasis, protection against oxidative stress, and modulates physiological and pathological processes, acting in synergy with classical antioxidant mechanisms. From an antioxidant perspective, melatonin exerts a dual mechanism of action: it directly scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS), and it also induces the expression of endogenous antioxidant enzymes [16, 17]. Melatonin also inhibits lipid peroxidation (LP), stimulates antioxidant enzymes, and reduces metal toxicity; it stabilizes mitochondrial activity and suppresses inflammatory signaling [18]. Moreover, melatonin and its metabolites act collectively to provide versatile antioxidant protection: their combined presence amplifies the neutralization of ROS, facilitates metal chelation, radical adduct formation, and repair of oxidatively damaged biomolecules, positioning the melatonin family as a natural defense system against oxidative stress [19].

Its lipophilic nature facilitates diffusion across membranes, allowing melatonin to neutralize free radicals in mitochondria and other cellular compartments, thereby reducing lipid peroxidation, preventing DNA damage, and preserving mitochondrial integrity [9]. In addition to this direct antioxidant action, melatonin modulates gene expression of crucial antioxidant enzymes such as cytosolic Cu/Zn-superoxide dismutase (SOD1), mitochondrial MnSOD (SOD2), glutathione peroxidase (GPx), and catalase (CAT). These enzymes act in concert to detoxify ROS: SODs catalyze the dismutation of superoxide anions into hydrogen peroxide, which is subsequently degraded into water and oxygen by GPx and CAT [16, 20]. By influencing these pathways, melatonin complements and amplifies the activity of the endogenous antioxidant network, rather than acting as an isolated regulator.

At physiological concentrations, melatonin predominantly exerts its antioxidant activity via gene regulation, whereas pharmacological levels potentiate its direct radical-scavenging effects. Recent studies reinforce that, beyond its recognized antioxidant activity, melatonin helps to preserve the structural integrity of cellular components, particularly membranes, mitochondria, and DNA [17, 20, 21]. A key example of this property is illustrated by the “antioxidant cascade” of melatonin, in which the indoleamine not only scavenges hydroxyl and peroxyl radicals to prevent the initiation and propagation of LP, but also generates metabolites such as cyclic 3-hydroxymelatonin (C3OHM), N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK), and N¹-acetyl-5-methoxykynuramine (AMK). These products retain significant radical-scavenging activity, thereby extending melatonin’s protective role against oxidative damage through successive reactions [22]. As shown in Fig. 1 (Ref. [10]), this cascade interrupts LP chain reactions and neutralizes reactive intermediates, highlighting melatonin’s unique advantage over classical antioxidants [10].

Fig. 1.

Mechanism of lipid peroxidation (LP) and melatonin’s antioxidant cascade. On the left, the initiation, propagation, and termination steps of LP are shown, leading to the generation of lipid radicals and lipid hydroperoxides (LOOH). On the right, melatonin’s antioxidant cascade is represented, where melatonin not only directly neutralizes reactive oxygen and nitrogen species (ROS/RNS) but also generates bioactive metabolites such as cyclic-3-hydroxymelatonin (C3OHM), N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK), and N¹-acetyl-5-methoxykynuramine (AMK). These metabolites further contribute to the suppression of oxidative stress, amplifying melatonin’s protective role. Illustration adapted with permission from Reiter et al. [10], Dual sources of melatonin and evidence for different primary functions; published by Frontiers Media S.A., 2024.

Its ability to contribute to the limitation of LP helps maintain membrane fluidity and selective permeability, which are essential for cell function and signaling. At the mitochondrial level, melatonin cooperates in preventing dysfunction by mitigating ROS accumulation, thereby preserving the integrity of the respiratory chain and ATP synthesis efficiency. Furthermore, it supports genomic stability by protecting both nuclear and mitochondrial DNA from oxidative damage—either by directly scavenging radicals or by enhancing DNA repair mechanisms [20]. These protective mechanisms are fundamental for maintaining cellular homeostasis, particularly under conditions of oxidative stress, and have been associated with melatonin’s protective effects on aging, neurodegeneration, and cancer [9, 21].

Rather than functioning alone, melatonin interacts with multiple signaling and defense pathways, exerting modulatory actions across apoptosis, immunoregulation, and mitochondrial processes. It can exert anti-apoptotic effects in normal tissues, while promoting apoptosis in malignant cells, highlighting its context-dependent role [23]. In the hematopoietic system, for example, melatonin protects progenitor cells from chemotherapy-induced apoptosis by stimulating Th2 cells to release IL-4, which in turn activates stromal cells to produce GM-CSF, thereby promoting cellular regeneration. In tumor cells, such as MCF-7, melatonin induces cell cycle arrest via the p53/p21^WAF1 pathway, balancing mitosis and apoptosis—demonstrating its dual role as a cytoprotective agent in normal cells and an antiproliferative factor in cancer cells [23]. Additionally, Florido et al. (2022) [24] detailed the mechanisms through which melatonin induces reactive ROS production in cancer cells, including interactions with calmodulin to activate iPLA2, inhibition of the AKT pathway leading to NRF2 degradation, modulation of mitochondrial sirtuin 3 (SIRT3), and stimulation of the mitochondrial respiratory chain via reverse electron transport. By increasing ROS while reducing antioxidant defenses, melatonin selectively promotes apoptosis in tumor cells, highlighting its potential as a complementary anticancer therapy.

Beyond its antioxidative and apoptotic regulation, melatonin contributes to immunomodulation. It regulates the function of diverse immune cells, including T and B lymphocytes, macrophages, neutrophils, and dendritic cells [25]. This indoleamine finely adjusts the balance between pro-inflammatory and anti-inflammatory cytokines, being capable of either enhancing immune responses against pathogens or suppressing chronic inflammation [26]. Mechanistically, this occurs through modulation of key intracellular signaling pathways such as NRF2, NF-$\kappa$B, and the NLRP3 inflammasome, leading to reduced expression of inflammatory mediators including TNF-$\alpha$, IL-6, and IL-1$\beta$ [27]. Such regulatory capacity is critically important in chronic inflammatory and degenerative diseases, where melatonin functions as part of a broader anti-inflammatory and immunoregulatory network.

A further aspect of melatonin’s biological role is its ability to regulate apoptosis—a key process for maintenance of tissue integrity and the elimination of damaged or potentially malignant cells. Melatonin promotes apoptosis in tumor cells by modulating key regulatory proteins such as Bax, Bcl-2, caspases, and p53, while also affecting mitochondrial membrane permeability and triggering cytochrome c release [9, 14]. Likewise, melatonin exerts anti-apoptotic and cytoprotective effects in normal cells subjected to oxidative or toxic stress, preserving cell viability and preventing irreversible damage [28]. This duality emphasizes its complementary value within endogenous defense mechanisms, particularly in conditions of oxidative stress.

Adding to its multifaceted role, recent studies have highlighted melatonin’s capacity to regulate mitochondrial biogenesis and function. By enhancing mitochondrial efficiency and reducing mitochondrial ROS production, melatonin further strengthens its antioxidant and cytoprotective effects [9, 29]. Therefore, melatonin emerges as an important component of the antioxidant and regulatory network, acting alongside classical enzymatic defenses and trace elements such as zinc.

In summary, melatonin is a versatile molecule, endowed with a broad spectrum of bioactive properties that contribute to maintaining homeostasis and protecting against physiopathological insults, in concert with other endogenous mechanisms. Its therapeutic potential has been extensively explored in various medical fields, with significant relevance in the treatment of neurodegenerative diseases, cancer, cardiovascular disorders, sleep disturbances, and chronic inflammatory conditions. This underscores the importance of advancing research focused on elucidating its molecular mechanisms and expanding its clinical applications [20].

Based on extensive experimental evidence, melatonin is considered a highly promising natural modulator of LP, a critical process mediated by ROS/RNS that compromises membrane integrity and generates toxic byproducts such as MDA and 4-HNE (Fig. 2). Melatonin exerts its antioxidant effect both directly, by neutralizing radicals such as •OH, ROO•, and ONOO⁻, and indirectly, by enhancing the expression and activity of SOD, CAT, GPx, while inhibiting pro-oxidant enzymes such as NADPH oxidase (NOX) and iNOS. Its metabolites, including AFMK and AMK, retain significant antioxidant capacity which sometimes exceeds that of melatonin, providing a cascading protective effect against LP progression. Furthermore, melatonin attenuates ferroptosis by modulating ROS production and iron metabolism.

Fig. 2.

Melatonin attenuates lipid peroxidation and ferroptosis through multiple antioxidant and regulatory mechanisms. Melatonin (MEL) exerts protective effects against ferroptosis by modulating reactive oxygen species (ROS) production and iron metabolism. Upon entering the cell via membrane receptors (MT1/MT2), melatonin directly scavenges ROS, including hydroxyl radicals (•OH) and superoxide anions (O₂•⁻), reducing oxidative stress and mitochondrial dysfunction. MEL also enhances mitochondrial ATP production and maintains redox homeostasis. Through upregulation of antioxidant defense systems—including superoxide dismutase (SOD1/2), glutathione peroxidase (GPx), catalase (CAT), and the NRF2 signaling pathway—melatonin promotes the attenuation of lipid peroxidation. GPX4 reduces lipid hydroperoxides, thereby inhibiting the accumulation of toxic lipid peroxidation products (e.g., MDA, 4-HNE) and preventing ferroptotic cell death. Additionally, melatonin interferes with iron metabolism by modulating transferrin receptor expression and iron uptake (Fe³⁺/Fe²⁺), thus limiting the Fenton reaction and downstream lipid peroxidation. Collectively, these actions highlight melatonin’s role in maintaining membrane integrity and preventing iron-dependent lipid damage and ferroptosis. GPX4, glutathione peroxidase 4; MDA, malondialdehyde; 4-HNE, 4-hydroxynonenal; NRF2, nuclear factor erythroid 2–related factor 2; GSH, reduced glutathione; GSSG, oxidized glutathione; ATP, adenosine triphosphate. The Fig. 2 was created in BioRender.com. Chuffa, L. (2025) https://BioRender.com/fd436c4.

Upon entering the cell via PEPT ½ oligopeptide transporters, GLUT4 receptor and/or diffusion, melatonin scavenges ROS, enhances mitochondrial ATP production, maintains redox homeostasis, and promotes antioxidant defense via SOD1/2, GPx, CAT, and NRF2 signaling. GPX4 reduces lipid hydroperoxides, preventing accumulation of toxic LP products and ferroptotic cell death. Melatonin also regulates transferrin receptor expression and iron uptake (Fe³⁺/Fe²⁺), limiting the Fenton reaction and subsequent LP, thereby maintaining membrane integrity and protecting against iron-dependent oxidative damage.

LP can trigger regulated cell death pathways, particularly apoptosis and ferroptosis, depending on context, location, and intensity. During apoptosis, LP products like 4-HNE modify regulatory proteins such as caspases and members of the Bcl-2 family and facilitate cytochrome c release from mitochondria [30, 31]. Cardiolipin, a highly unsaturated mitochondrial phospholipid, is especially sensitive to LP; its oxidation promotes Bax translocation and mitochondrial permeabilization, initiating intrinsic apoptosis [32]. LP can also act as a resolution signal, promoting non-inflammatory clearance of damaged cells, which is essential for tissue remodeling, embryogenesis, and immune responses [12]. When deregulated, LP leads to pathological cell death such as ferroptosis, characterized by iron-dependent accumulation of lipid peroxides and GPX4 failure [33]. Melatonin counteracts ferroptosis by reducing iron uptake, scavenging ROS, and reinforcing GPX4 activity, serving as a crucial regulator of ferroptotic sensitivity in cancer and degenerative diseases [34].

Mitochondria are both sources and targets of ROS, and their imbalance triggers oxidative stress, apoptosis, necrosis, and chronic inflammation [35, 36]. Melatonin acts as a central protector against LP, both directly and indirectly. Its high mitochondrial concentration (~100$\times$ plasma) supports local organelle protection, and melatonin can be synthesized in mitochondria from tryptophan and metabolized to AFMK [14, 35, 37]. It preserves mitochondrial membrane potential, reduces ischemia-reperfusion-induced ROS, protects cardiolipin from oxidation, and regulates mitochondrial biogenesis and mitophagy [14, 35, 38]. In experimental models, melatonin decreased LP, preserved ATP, and enhanced antioxidant enzymes, while reducing protein carbonylation and maintaining membrane fluidity and function [1, 2, 39, 40].

In HepG2 liver cancer cells, melatonin increases ROS and triggers mitochondrial dysfunction and cell death, while protecting neighboring healthy cells [41]. Similarly, Florido and co-workers [24] demonstrated that specific concentrations of melatonin can generate ROS in cancer cells, promoting programmed cell death and enhancing chemotherapy sensitivity, without affecting normal tissues. Chok et al. [42] further showed that melatonin induces ROS-mediated autophagy in colorectal cancer cells, causing endoplasmic reticulum stress and selective tumor cell death. These findings indicate that melatonin acts as a context-dependent redox modulator, preserving normal cell integrity while exploiting the oxidative vulnerability of cancer cells, supporting its potential as an adjuvant therapeutic agent in oncology.

Melatonin therapy can be administered orally, by injection, topically, or in nanoencapsulated form. Various pharmaceutical formulations of melatonin have been explored with the aim of improving its bioavailability, stability, and therapeutic efficacy, especially in conditions related to oxidative stress. Oral administration is widely used, particularly in the treatment of sleep disorders and in antioxidant protocols, due to its practicality and safety. Clinical studies have shown that co-supplementation with melatonin, magnesium, and zinc improves sleep quality in elderly individuals, highlighting the role of micronutrients supporting melatonin synthesis and function [71]. However, this route presents limited bioavailability (9% to 33%) because of the first-pass hepatic metabolism [72, 73].

In experimental models, injectable administration—mainly via intraperitoneal or intravenous routes—has been used to achieve faster and higher plasma levels, being particularly effective in acute scenarios, such as in models of cerebral or hepatic ischemia-reperfusion [74]. Topical melatonin formulations, in turn, have shown efficacy in skin diseases and wound healing processes, benefiting from melatonin’s ability to cross the epidermal barrier and exert localized antioxidant and immunomodulatory effects [73]. More recent advances include the use of nanoencapsulated melatonin formulations, which enable controlled drug release, greater chemical stability, and preferential targeting to intracellular compartments, especially mitochondria. Nanoencapsulated melatonin has proven more effective in neutralizing reactive oxygen and nitrogen species, in addition to showing greater antitumor and neuroprotective activity, as evidenced by studies in experimental models [9, 73].

Several preclinical experimental models have demonstrated the efficacy of melatonin as an antioxidant agent and cellular protector against various pathophysiological conditions characterized by oxidative stress and LP. These studies cover hepatic, neurodegenerative, oncological, and metabolic models, strengthening the understanding of its molecular mechanisms and potential clinical applications (Table 1, Ref [66, 74, 75, 76, 77]).

Aykutoglu et al. [75] (Table 1) demonstrated that endothelial cells (HUVECs) exposed to homocysteine showed increased cell viability, reduced lipid peroxidation (TBARS/MDA) levels, and lower caspase activation, associated with an upregulation of Bcl-2 expression. Moreover, treatment with melatonin (10 µM) was more effective than vitamin E (50 µM) in reducing LP and apoptosis, documenting the superior antioxidant and antiapoptotic potential of melatonin.

In the hepatic context, Aranda et al. (2010) [76] (Table 1) investigated the effect of melatonin in rats exposed to carbon tetrachloride (CCl₄), a potent hepatotoxic agent that induces LP. Treatment with melatonin (10 mg/kg, intraperitoneally) promoted a significant reduction in MDA and 4-HDA levels, classic biomarkers of lipid damage. Furthermore, melatonin preserved the fluidity of hepatic cell membranes and prevented morphological alterations such as necrosis and cellular ballooning. Even at pharmacological doses, no side effects were observed, confirming its high safety profile. These findings demonstrate melatonin’s protective action on tissues highly susceptible to oxidative injury by xenobiotics.

In models of brain aging, García et al. (2011) [66] (Table 1) used mice from the SAMP8 (accelerated senescence) and SAMR1 (normal aging) strains to evaluate the chronic effects of melatonin (10 mg/kg/day). Treated animals showed significant improvement in mitochondrial membrane fluidity, reduction in LP levels, and lower expression of cathepsin D, a lysosomal protease associated with neuronal apoptosis. Restoration of the GSH/GSSG ratio was also observed, indicating recovery of redox homeostasis. These data suggest that melatonin exerts neuroprotective effects associated with preservation of mitochondrial function and attenuation of oxidative aging.

In metabolic disorders, especially in the context of experimental diabetes, Winiarska et al. (2006) [77] (Table 1) compared the efficacy of melatonin (1 mg/kg) to N-acetylcysteine (NAC, 10 mg/kg) in alloxan-induced diabetic rabbits. Melatonin proved more effective in reducing hydroxyl radicals, restoring the GSH/GSSG ratio, and activating antioxidant enzymes such as GPx, GR, and GST. On the other hand, NAC only promoted an increase in GSH levels without significantly impacting other oxidative stress markers. This highlights the broader and mitochondria-targeted action of melatonin, especially relevant for tissues with high redox disruption, such as those often affected in renal and hepatic contexts.

In the setting of acute neurological injury, Sabbaghziarani et al. (2024) [74] (Table 1) used a cerebral ischemia-reperfusion model in Wistar rats subjected to middle cerebral artery occlusion (MCAO). Administering melatonin (5 mg/kg), NAC (50 mg/kg), or a combination of the two revealed that melatonin alone induced the antioxidant NRF2 pathway, increased SOD, GPx, and catalase enzymes, and significantly reduced infarct volume. Although NAC showed antioxidant effects, its action was less robust and limited to increasing total glutathione. The combined treatment produced the best results, with marked reduction in lipid peroxidation (MDA), decreased brain damage, and improved functional recovery, suggesting therapeutic synergy.

These experimental models confirm that melatonin consistently acts as a modulator of LP, with direct and indirect effects on mitochondrial biogenesis, enzymatic antioxidant pathways, apoptosis, and cellular plasticity. Its ability to cross biological barriers, such as the blood–brain barrier, and its mitochondrial affinity confer significant advantages over classical antioxidants. These findings support the translational potential of melatonin as a therapeutic agent in clinical conditions marked by oxidative stress, such as hepatic diseases, neurodegenerative disorders, cancers, and metabolic disorders.

Despite the widespread use of melatonin as a sleep aid and therapeutic supplement, recent evidence identifies several likely concerns regarding its safety, efficacy, and regulatory oversight. Studies in pediatric populations have reported non-serious adverse effects such as somnolence, headache, and dizziness, emphasizing the need for careful dose management and monitoring in vulnerable groups [78, 79]. Analyses of commercially available supplements have revealed substantial discrepancies between labeled and actual melatonin content, with some products containing several times the declared dose, raising serious safety concerns [80]. Regulatory data from the CDC’s Morbidity and Mortality Weekly Report reinforce these findings, warning that unregulated melatonin products, especially those marketed for children, may pose health risks due to extreme variability in dosage [81]. Collectively, these studies underscore the importance of cautious clinical use, stringent quality control, and further research to establish safe and effective therapeutic protocols for melatonin administration.

LP is a central process in the onset and progression of numerous chronic diseases, including cancer, neurodegenerative disorders, and cardiovascular conditions. Melatonin emerges as a highly promising molecule in this context, due to its potent antioxidant properties and its capacity to modulate inflammatory and apoptotic pathways. Its amphiphilic nature and ability to cross cellular membranes and target mitochondria—organelles particularly susceptible to oxidative stress—further enhance its therapeutic potential.

Melatonin functions as a multifaceted antioxidant, neutralizing ROS, modulating antioxidant enzymes, and influencing inflammatory signaling, apoptosis, and autophagy. Importantly, it can restore redox balance without disrupting physiological processes mediated by LP, thus maintaining essential cellular signaling and homeostasis. The protective actions of melatonin and its metabolites, such as AFMK and AMK, suggest an efficient antioxidant cascade potentially surpassing the limitations of conventional antioxidants. Its excellent safety profile, including the ability to cross the blood–brain barrier, positions melatonin as an attractive candidate for managing neuroinflammatory, neurodegenerative, and oxidative-stress-associated disorders.

Although preclinical evidence strongly supports melatonin’s antioxidant and lipid-protective actions, clinical research remains limited and fragmented. To enhance its translational potential, future clinical studies should focus on large-scale, well-controlled randomized trials (RCTs) with standardized LP biomarkers (e.g., MDA, oxLDL (oxidized low-density lipoprotein), 4-HNE). Stratification by disease type (metabolic syndrome, oncology, neurodegeneration), route of administration (oral vs. targeted delivery), and dosing regimen will be critical. Biomarker-guided approaches could identify patient populations most likely to benefit, paving the way for personalized therapeutic strategies.

Table 2 (Ref. [82, 83, 84, 85, 86, 87]) summarizes key clinical studies that have investigated melatonin’s effects on sleep, neurodegeneration, cardiovascular risk, and oncology, highlighting dosing strategies, biomarkers, stratification criteria, and relevant clinical outcomes. This compilation illustrates the current state of clinical translation and supports the rationale for precision medicine approaches with melatonin.

Melatonin is clearly a multifunctional molecule with significant potential in the prevention and treatment of diseases associated with oxidative stress, chronic inflammation, and LP. Its antioxidant, anti-inflammatory, and anti-apoptotic properties, combined with its ability to target mitochondria and cross biological barriers, provide a compelling rationale for its therapeutic application in cancer, cardiovascular disorders, neurodegeneration, and metabolic diseases.

Preclinical evidence strongly supports melatonin’s role in modulating LP, preserving mitochondrial integrity, and regulating apoptotic and ferroptotic pathways. Moreover, its metabolites contribute to an efficient antioxidant cascade that may overcome limitations of conventional antioxidants. Clinical studies revealed the diversity of dosing strategies, patient populations, biomarker applications, and observed outcomes, highlighting the translational potential of melatonin.

Importantly, melatonin has an excellent safety profile, especially in adults, even at supraphysiological doses, making it a viable candidate for both adjunctive and standalone therapies. Future research should prioritize personalized approaches, considering dose, timing, route of administration, and patient stratification based on biomarkers and disease type. Integration with advanced delivery systems—such as nanoparticles, extracellular vesicles, or targeted carriers—may further enhance efficacy and adherence.

In conclusion, melatonin represents a promising molecule capable of bridging basic mechanistic insights and clinical applications, positioning it as a potential cornerstone of precision medicine approaches for oxidative-stress-related diseases. Future studies should focus on large-scale, biomarker-guided trials to establish robust clinical protocols and optimize therapeutic outcomes.

OAJV and DAPCZ were primarily responsible for the writing and critical revision of the manuscript, ensuring conceptual clarity and cohesion throughout the text. LGAC and RJR contributed substantially to the critical review and enhancement of visual elements, refining both the scientific content and its presentation. OAJV, DAPCZ, LGAC, and RJR contributed to the conceptualization. RJR served as the original mentor of the project, guiding its development from the initial stages with scientific insight and supervision. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

The authors are grateful to the São Paulo Research Foundation (FAPESP) and the National Council for Scientific and Technological Development (CNPq).

The authors received financial support as follows: LGAC (CNPq Process number 306117/2023-1; FAPESP Process number 2021/12971-7).

The authors declare no conflict of interest.

During the preparation of this work, the authors used ChatGPT in order to check spelling and grammar. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.