Introduction

Reduction and oxidation reactions (redox) control almost all aspects of life [1]. Oxidation is a fundamental part of aerobic life and our metabolism; thus, reactive species (RS) of oxygen (ROS), nitrogen (RNS), chlorine, bromine, iron, and sulfur are formed as by-products of this type of metabolism whose effects are counteracted by the reactions of reduction [2, 3]. Therefore, RS can be produced naturally or due to some biological dysfunction, such as during intensive physical activity, exposure to microbial infections that involve the activation of phagocytes, the action of pollutants/toxins such as cigarette smoke, alcohol, ionizing and UV radiation, pesticides, and ozone [4].

Historically, RS were believed to function exclusively as agents of cellular damage, reacting indiscriminately with lipids, proteins, and DNA [5, 6]. However, over the past two decades, there has been a growing appreciation of the role of ROS and RNS as mediators of cellular signaling, regulating numerous physiological responses [1, 2, 7]. The phenomenon termed hormesis describes a dose–response relationship to stressors, with a low-dose leading to stimulation of stress resistance mechanisms, thus enhancing the cellular capacity of preservation and repair and a high dose being detrimental, causing inhibition and cell damage [8, 9]. Therefore, biological systems present a dynamic evolutionary adaptive strategy depending on dose-time response [9]. The molecular recognition mechanisms occur at the atomic level. They operate in signaling through chemical reactions that lead to covalent modifications of proteins [10], promoting an expansion of the potential number of specific recipients [11].

The versatility of these molecules, concerning their properties and mobility within cells, is one of the significant advantages that is believed to be responsible for the evolutionary conservation of this type of signaling [12]. Moreover, as part of a highly conserved cellular signaling network, they are integrated with several signaling pathways, including the protective responses to ROS-induced oxidative stress. In this scenario, it has become apparent that moderate elevations in ROS levels (eustress) are essential for regulating processes, such as cell proliferation, apoptosis, and gene expression, through the transcription factor (TF) modulations [2, 4]. Under pathophysiological conditions, the RS production exceeds this physiological level, and only then does oxidative damage accumulate (distress), a process observed in many pathologies [1, 13]. Thus, redox homeostasis, described as “the golden mean of healthy living” [14], is indispensable for cell function and viability, so there is considerable evidence showing that oxidative damage is related to the primary or secondary pathophysiological mechanisms of various diseases [1, 13].

Regulation for such homeostasis can occur by modifying the activity of metabolic enzymes and TFs and through gene expression and epigenetic modifications [1, 15]. Therefore, this complex regulation involves a finely regulated network of redox reactions, post-translational modifications (PTMs), and their cellular outputs. This review will focus on the TF aspect of this regulation, more specifically, the Forkhead Box (Fox) subclass O3 (FoxO3), an extensively studied TF that shows a promising correlation with the redox metabolism and several pathological diseases associated with a redox disbalance [16]. Thus, this review aims to show that FoxO3 is a crucial modulator in redox metabolism by evidencing some pathways to how this TF and ROS regulate each other.

General aspects of FoxOs

The members of the FoxO family (FoxO1, 3, 4, and 6) are widely distributed throughout multiple species, ranging from yeasts to human beings [16, 17]. All four isoforms recognize and bind to the same FoxO-responsive sites, called "forkhead-responsive DNA elements" (FHRE), in the promoter region of target genes. Thus it is not surprising that FoxO isoforms have some overlapping activities, which results in a certain degree of redundancy [18]. However, there are also isoform-specific effects, as evidenced in studies with FoxO-isoform-specific knockout mice [19]. Nevertheless, there are also cell- and tissue-specific effects of the four FoxO isoforms due to differences in their expression levels and regulation [20]. FoxOs can be considered multitasking proteins as they play pleiotropic roles in a variety of physiological and pathological processes by regulating multiple gene regulatory networks involved in the modulation of numerous aspects of cellular metabolism, including fuel metabolism, cell death, and stress resistance (Fig. 1) [16, 21].

Fig. 1
figure 1

FoxOs as homeostasis regulators. Overview of FoxO transcription factors' roles in a wide range of cellular processes, which are generally regulated by external changes that disturb homeostasis, including metabolic stress (e.g., starvation) and oxidative stress, the last one being highlighted (upper right quadrant). Source: by the authors

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Regarding redox homeostasis, FoxO3 is an essential TF due to its well-established role as a central mediator of cellular response to stress in different animal models [22]. Indeed, FoxO3 is a known core regulator of cellular homeostasis, stress response, and longevity, as it can modulate various stress responses upon nutrient shortage, oxidative stress, hypoxia, heat shock, and DNA damage. Therefore, we can link its role to increased lifespan by modulating stress responses upon oxidative stress, DNA damage, nutrient shortage, and caloric restriction [23].

In regard to cellular defense against oxidative stress, FoxO3 has a well-established role in regulating the expressions of many antioxidants, including catalase (CAT), Zinc and manganese superoxide dismutase (Zn- and Mn-SOD), peroxiredoxins 3, and 5 (PRDX3 and PRDX5), and glutathione peroxidase (GPx) [24,25,26,27,28]. Furthermore, the expressions of thioredoxin 2 (Trx2) and thioredoxin reductase 2 (TrxR2) were also revealed to be regulated by FoxO3 [28]. Thus, protecting cells from oxidative stress by increasing ROS scavengers contributes to extending the organismal lifespan. Moreover, FoxO3 protein can act in promoting cell growth inhibition (by enhancing the expression of various CDK inhibitors) [29,30,31,32] or apoptosis (pro-apoptotic genes are activated) [33,34,35,36,37] when upon intense oxidative stress. Hence, this demonstrates that activation of FoxO3-dependent transcription in response to oxidative stress depends on the severity of the stimulus [16] (Fig. 2).

Fig. 2
figure 2

FoxO and Oxidative stress. The activity of FoxO proteins is differentially controlled in specific tissues according to oxidative stress intensity (external stimuli) through the modification of protein levels, subcellular localization, DNA-binding, and transcriptional activity of FoxO. In cases of medium oxidative stress stimuli, FoxOs proteins mediate protective cellular mechanisms by increasing the expression of ROS scavengers. On the other hand, under high oxidative stress stimuli, FoxOs promote cell growth inhibition (by enhancing the expression of various CDK inhibitors) or apoptosis (pro-apoptotic genes are activated). ATG12, autophagy related 12; BBC3, BCL-2-binding component 3 gene; BCL2L11, Bcl-2-like protein 11, commonly called BIM; Bcen1, beclin 1; BCL6, B cell lymphoma 6; BNIP3, BCL2 Interacting Protein 3; CAT, catalase; CCND1, cyclin D1; CCNG2, cyclin G2; CDKN1A, cyclin-dependent kinase inhibitor 1A; CDKN1B, cyclin-dependent kinase inhibitor 1B; CDKN2A, cyclin-dependent kinase inhibitor 2A; CDKN2B, cyclin-dependent kinase inhibitor 2B; FASLG, Fas ligand; FoxO, forkhead box O protein; GABARAPL1, GABA type A receptor associated protein like 1; GADD45A, growth arrest and DNA damage inducible alpha; GPx, glutathione peroxidase; Mn-SOD, manganese superoxide dismutase; PMAIP1, phorbol-12-myristate-13-acetate-induced protein 1; PRDX3, peroxiredoxin 3; PRDX5, peroxiredoxins 5; PTEN, induced putative kinase 1; PUMA, p53 up-regulated modulator of apoptosis; p15; p19; p21; p27; p53, up-regulated modulator of apoptosis; p130; RBL2, RB transcriptional corepressor like 2; SENP, sentrin-specific protease 1; TNF, tumor necrosis factor; TNFSF10, tumor necrosis factor superfamily member 10; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TrxR2, mitochondrial thioredoxin reductase; Trx2, mitochondrial thioredoxin; Zn-SOD, zinc superoxide dismutase. *For a review of FOXO-regulated genes, see [38]. The authors created this figure by adapting images from Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com)

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Regulatory mechanisms of FoxO3 expression and activity

FoxOs are transcriptional regulators that activate gene expression in most cases. Their activities and cellular functions are regulated by various mechanisms, such as non-coding RNAs (ncRNAs), protein–protein interaction, and PTMs, such as phosphorylation, acetylation, ubiquitination, and methylation [39], as well as the oxidative modifications [40, 41].

Post-translational modification

Of particular interest to human health, FoxO3 is under the control of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, whose activation results in the phosphorylation at three conserved residues (Thr32, Ser253, and Ser315) of FoxO3 [42]. This PTM causes FoxO3 exclusion from the nucleus, and its association with the chaperone 14–3-3, ultimately blocking re-entry into the nucleus [43, 44]. Hence, contrary to PI3K/AKT, other signaling pathways can positively regulate FoxO3, for example, through stress-kinase (JNK, MST1)-mediated phosphorylation [16, 21]. This antagonistic signaling pathway occurs in response to oxidative stress. Thus, in this case, the phosphorylation of FoxO3 by MST1 or JNK at alternative PTM sites dissociates 14–3-3, promoting FoxO3’s localization to the nucleus. In other words, in the absence of AKT phosphorylation, the nuclear accumulation of FoxO3 facilitates its interaction with gene regulatory regions, inducing the expression of its target genes. However, only this subcellular localization per se presumably does not result in the total transcriptional activity of FoxO3 [45].

Other kinases, such as serum- and glucocorticoid-inducible kinase (SGK), cyclin-dependent kinases (CDKs), and mitogen-activated protein kinase (MAPK) can also phosphorylate FoxO3 [45]. For example, the mammalian MAPK family is comprised of three well-characterized subfamilies, including extracellular signal-regulated kinase (ERK) [46], which can directly phosphorylate FoxO3 at three different sites (Ser294, Ser344, and Ser425), leading to its degradation in a murine double minute 2 (MDM2)-dependent manner [47]. From this data, it is possible to observe that each kinase recognizes specific motifs within FoxO3, and thus, the phosphorylation can lead to opposing effects depending on the target residue.

Acetylation is another widely occurring dynamic PTM that modulates the functions of proteins [48]. In regards to FoxO3 role, its acetylation at Lys242 and Lys245 sites by calcium response element-binding protein (CBP)/p300 significantly reduces their DNA-binding capacity and induces their cytoplasmic localization [49]. It is noteworthy that the effect of acetylation is negatively regulated by histone deacetylases (HDACs), which remove the acetyl groups from histones and non-histone proteins through an enzymatic reaction [50]. For instance, Sirtuin 1 (SIRT1)—a subclass of HDACs with nicotinamide adenine dinucleotide-dependent deacetylation activity, was reported to maintain FoxO3 nuclear localization, following exposure to stress stimuli, by mediating its deacetylation via directly interacting with FoxO3 [51].

Protein methylation is also a reversible process that plays a crucial role in modulating protein characteristics, such as activities, translation, and localization [52]. For example, Calnan et al. demonstrated that FoxO3 methylation by the SET domain containing lysine methyltransferase 9 (Set9) at Lys270 and Lys271 resulted in the reduction of the DNA-binding activity and transactivation of FoxO3 [53]. Ubiquitination is a reversible PTM whose primary function is to mediate protein degradation via the ubiquitin–proteasome pathway [54]. In this way, ubiquitin–proteasome-mediated protein degradation plays a crucial role in regulating several cellular processes, such as cell cycle progression, transcriptional regulation, and DNA repair [55]. Thus, the interplay between molecular redox signaling and the ubiquitin–proteasome system are intertwined to pathophysiological processes in human diseases [56]. For example, constitutive photomorphogenic 1 (COP1) promotes the ubiquitination and degradation of FoxO3, decreasing the expression of its target genes [57, 58]. Another essential and complex PTM is glycosylation. This PTM plays a crucial role in regulating FOXO3 substrate structure, function, and physical properties [59]. The most common mechanisms of protein glycosylation are N-glycosylation and O-glycosylation [60]. Shin et al. demonstrated the occurrence of O-glycosylation sites in the FoxO3 transactivation domain. Additionally, they showed that the O-glycosylation at Ser284 significantly inhibited p21-mediated cancer cell growth by targeting the MDM2-p53-p21 axis [61].

Furthermore, in redox signaling, low levels of ROS can cause the oxidation of specific cysteine-thiols, which can both activate [62] or inactivate [63] proteins. This signaling is an exciting concept, as it allows the redox state-dependent regulation of TFs by introducing a covalent bond with cofactors that, under reducing conditions, would hardly interact [41]. Putker et al. demonstrated that FoxO3 forms a disulfide-dependent heterodimer with the nuclear import receptors, Importin-7 (IPO7), and Importin-8 (IPO8). These interactions are required for efficient nuclear import of FoxO3 under oxidative conditions (i.e., the interaction required for ROS-induced nuclear translocation of FoxO3). Thus, the authors proposed that ROS could directly regulate FoxO3 nuclear importation by mediating its heterodimerization in a redox-sensitive and disulfide-dependent manner through FoxO3’s cysteine oxidation [64].

Meanwhile, Hopkins et al. demonstrated that FoxO3's disulfide heterodimer with PRDX1 also influences the nuclear localization of this TF. Thus, allowing a rapid and precise regulation of FoxO3 in response to oxidative stress. The authors propose that PRDX1 constitutes an essential step for maintaining a redox signaling-dependent cytoplasmic reservoir of FoxO3 that is readily available in the face of high levels of H2O2 [65]. This observation allowed FoxO3s proteins to be classified as "Speroxiredoxinylated", a term coined to demonstrate the interaction between peroxiredoxins with redox reaction cysteines in general [66].

These examples show that FoxO3 functions are affected via distinct mechanisms. Thus, demonstrating that these PTM patterns produce specific biological effects. Therefore, as exemplified above, these reversible PTMs are dynamic and can modulate FoxO3 function by altering its subcellular localization and changing its stability and DNA-binding affinity [67]. These PTM are also affected by redox-regulatory processes (i.e., oxidative inactivation of Akt [68]), which adds another layer of complexity associated with FoxO regulation. As an example, the phosphorylation mediated by PI3K/AKT pathway is affected by ROS at several levels, including oxidative inhibition of protein tyrosine phosphatase-1B (PTB-1B), or of the lipid and protein phosphatase, PTEN, and even oxidative inactivation of AKT was described (reviewed in [68, 69].

Non‑coding RNAs influence FoxO3 regulation

According to the ENCODE (Encyclopedia of DNA Elements) project and later reports, about 80% of the human genome can be transcribed into non‑coding RNAs (ncRNAs). In general, ncRNAs are a range of RNA molecules that act on multiple biological processes, pathological or physiological, through regulating gene expression or PTM. These molecules are derived from eukaryotic transcription from different genomic regions and RNA processing that produces various ncRNA species that are grouped into different categories according to size and function, such as long ncRNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), and others (reviewed in [70]). In the last few years, it has become clear that such molecules significantly influence the activity and expression of FOXO in different pathological conditions.

It is well established that different miRNAs can regulate FOXO transcripts in various processes due to their pleiotropic influence, such as in neurodegenerative diseases, longevity, cancer, and many others [16]. Different miRNAs targeting FOXO mRNAs are involved in tumor promotion, growth, or metastasis, such as miR-182. Under physiological conditions, miR-182 can down-regulate FOXO expression, allowing cell proliferation and cycle progression. On the other hand, when inhibition of proliferation, cell cycle arrest, or apoptosis is intended, a down-regulation of miR-182 may be required. Examples of miR-182 action occur in lung cancer [71] and melanoma [72]. Furthermore, researchers have shown that miR-182 also contributes to FOXO3 regulation in skeletal muscle during chronic diseases associated with elevated glucocorticoid production, such as diabetes and chronic kidney disease [73].

He et al. demonstrated that MiR-25 could directly target the 3′UTR of FOXO3 mRNA, inhibiting its expression and resulting in enhanced resistance of gastric cancer cells to cisplatin [74]. A similar result was demonstrated in colorectal cancer using another miRNA, the miR153 [75]. Moreover, in another report about this later type of cancer, miR-592 promotes metastasis, in part, by targeting FOXO3 [76]. The direct bind of MiR-96 to the 3′-UTR of FOXO3 mRNA inhibits its function [77]. It can also promote, in response to collagen matrix via reducing FOXO3 and its targets (p27, p21, and Bim), the pathologically altered idiopathic pulmonary fibrosis (IPF) phenotype [78].

In regards to the lncRNAs, a recent study demonstrated that FOXO3 expression could be negatively regulated by miR-27a-3p and positively regulated by lncRNA X inactivate‑specific transcript (XIST), an RNA associated with cerebral ischemia/reperfusion ( I/R) injury that binds with miR-27a-3p to upregulate FOXO3 [79]. Wang et al. revealed that lncRNA plasmacytoma variant translocation 1 (PVT1), directly interacting with FoxO3, can modulate its transcription activity. The enhanced FoxO3 activity was achieved by the knockdown of PVT1, which considerably downregulated its phosphorylation level by facilitating SCP4-mediated FoxO3 dephosphorylation. The upregulation of FoxO3, due to PVT1 knockdown, also enabled the apoptosis of granulosa cells [80].

Moreover, overexpression of the lncRNA growth arrest-specific transcript 5 (GAS5) resulted in a significant elevation of FoxO3 protein level, which was attenuated by the addition of miR-9, demonstrating that GAS5 promoted FOXO3 expression by competitively sponging miR-9. Meanwhile, the knockdown of GAS5 significantly reduced the expression of FoxO3 protein, and the depletion of miR-9 in bEnd restored it [81]. Zhai et al. identified a new lncRNA, URRCC, as a part of a feedback loop with EGFL7/P-AKT/FoxO3 signaling. In renal cell carcinoma samples, URCC expression is upregulated, promoting clear cell renal carcinoma (ccRCC) cell proliferation, invasion, and reduced overall survival of ccRCC patients. Mechanistically, URRCC can acetylate histone H3 of EGFL7 promoter, increasing AKT signaling pathway and consequently suppressing downstream FoxO3 signaling through AKT phosphorylation, which was demonstrated to enhance cell proliferation and invasion in vitro and in vivo. On the other hand, FoxO3 can directly bind to the URRCC promoter region, downregulating its expression [82].

Lastly, studies have shown that circRNAs can be crucial modulators of FoxOs. Recently, Yu et al. demonstrated that circRNA CRIM1 overexpression significantly repressed the migration and invasion of bladder cancer cells by up-regulating FOXO3 expression via sponging miR-182, a miRNA capable of modulating FoxO3 activity. Moreover, miR-182 expression was elevated in bladder cancer tissues and cell lines, while CRIM1 and FOXO3 expressions were decreased [83].

Another layer of complexity arises from the fact that circ-FOXO3 can modulate FoxO3 activity. Du et al. presented some exciting findings about circ-FOXO3. Their study showed that in patient tumor samples and a panel of cancer cells, circ-FOXO3 was minimally expressed. However, circ-FOXO3 expression significantly increased during cancer cell apoptosis, which can be explored as the possibility of inhibiting tumor growth with the delivery of circ-FOXO3 plasmid. Moreover, silencing endogenous circ-FOXO3 contributed to cell viability, although ectopic expression of this RNA led to stress-induced apoptosis and repression of the growth of tumor xenografts. In addition, circ-FOXO3 expression elevated FoxO3 protein levels but inhibited p53 levels by promoting MDM2-induced p53 ubiquitination and degradation, leading to a decrease in p53. Due to low binding affinity to FoxO3, circ-FOXO3 avoided MDM2 from inducing FoxO3 ubiquitination and degradation, maintaining high levels of this TF that subsequently caused cell apoptosis by upregulation of its downstream target PUMA [84].

Overview of the relationship between free radicals and disease

As previously discussed, oxidative stress emerges from an imbalance of oxidative to reducing species, being also better defined as a perturbation of redox signaling [4]. The redox imbalance from chronic oxidative stress leads to significant PTM oxidative modifications in crucial biomolecules, such as lipid peroxidation, protein carbonylation, carbonyl (aldehyde/ketone) adduct formation, nitration, sulfoxidation, DNA impairment such as strand breaks, or nucleobase oxidation yielding 8-oxo-20-deoxyguanosine. Moreover, with the accumulation of these damaged biomolecules, healthy cells of the body lose their function and structure (reviewed in [85]).

In recent decades, the significance of oxidative stress has become increasingly recognized; thus, we can find stress-related diseases in virtually every organ [86]. Therefore, it is widely accepted that oxidative stress influences the establishment of multiple mechanisms by which oxidants contribute to cellular damage in various diseases, including atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer’s disease, and cancer [87]. In other words, it is essential to highlight the extent to which oxidative stress participates in the pathology of such diseases is quite variable. However, the effectiveness of therapeutic alternatives that increase antioxidant defense is still limited to some conditions. Thus, this section will focus on evidencing the relationships between oxidative stress and FoxO3 in different diseases.

As stated above, one of the primary mechanisms through which oxidative stress contributes to a disease involves the production of ROS (e.g., •OH, ONOO− and HOCl) that directly oxidize macromolecules, including membrane lipids, structural proteins, enzymes, and nucleic acids, leading to aberrant cell function and death. Another important mechanism of oxidative stress is aberrant redox signaling, in which non-physiological production of ROS (e.g., H2O2) can cause redox signaling to go awry [1]. Despite the role of oxidative stress in many diseases not being incompletely understood, a tentative categorization has been made: first, oxidative stress as the primary cause of pathology (e.g., atherosclerosis—oxidative stress is responsible for the conversion of LDL cholesterol into the oxidized-LDL, which has a crucial role in the development of atherosclerosis); second, oxidative stress as the secondary contributor to disease progression (such as in COPD, hypertension, and Alzheimer disease by disturbing various signaling pathways and thus, affecting multiple biological processes) (reviewed in [88]).

Additionally, in diseases caused by oxidative stress, the wide range of the pathological role of free radicals was didactically categorized, by some authors, into two major groups [89]. On one side, we have the diseases characterized by “inflammatory oxidative conditions” and enhanced activity of either NAD[P]H oxidase (leading to atherosclerosis and chronic inflammation) or xanthine oxidase-induced formation of ROS (implicated in ischemia and reperfusion injury). In this group, we can see that the reaction of the biomolecules and the free radicals will lead (directly or indirectly) to the disease, such as in the case of atherosclerosis, in which the malondialdehyde (MDA), a product of lipid peroxidation, reacts with low-density lipoproteins [90].

On the other hand, there are diseases characterized by pro-oxidants shifting the thiol/disulfide redox state and impaired glucose tolerance, also known as “mitochondrial oxidative stress” conditions (cancer and diabetes mellitus). To further exemplify, we can take cancer as a model. ROS contributes to the initiation and progression of carcinogenesis through the infliction of ROS-dependent mutations in DNA, which include base modifications to the activation of oncogenes [91].

The intrinsic relationship between the severity of different diseases and the imbalance between pro-oxidants and natural defenses suggests that antioxidant therapy represents a promising path for treatment. This strategy could be achieved by two means, through the use of natural antioxidants originating from an exogenous source, such as foods or dietary supplements (e.g., vitamins C and E) [92] or the synthesis of endogenous antioxidants, such as SOD [93]. The problem with the first option is known as the “antioxidant paradox”, which is the adverse effect resulting from the ingestion of a high concentration of antioxidants, as seen in some studies where the antioxidant treatment aggravated the oxidative damage and worsened the patient's condition (reviewed in [94]). The second alternative also presents challenges because proteins and enzymes generally make very poor drugs. Among the reasons for this “poverty”, we can cite the high cost of production, the possible immunogenicity, problems associated with purification and stability, non-availability by oral administration, and poor pharmacokinetic properties, including toxic, mutagenic effects, and possible side effects [95, 96].

In the search for another alternative, TFs that act on energy efficiency, cell resistance to stress, and also cell repair, such as FoxO3, has been gaining prominence due to their role in the redox code. The term ‘‘Redox Code’’ is a four principles code that applies to the redox organization of cells, tissues, and organisms, ultimately extending to all living matter (extensively reviewed in [13]). This code defines the operations of genetic codes and histones in the organizational structure, differentiation, and adaptation of an organism [13]. Therefore, they act in the modulation of complex networks that control signaling and cellular metabolism, thus being a fascinating mechanism in the development of new therapeutic strategies for diseases in which oxidative stress and inflammation play an essential role [97,98,99].

The FoxO3 proteins are considered a desirable therapeutic target because of their integral ability to control cell proliferation, metabolism, and survival [100, 101]. Therefore, FoxO3 activators, such as Resveratrol, are currently gaining attention. Studies performed by Franco et al. evidence the beneficial effects of its use [102]. In this study, this polyphenolic-stilbene enhanced erythroid cell maturation and decreased red cell membrane oxidative damage and anemia in β-thalassemic mice. In addition, resveratrol upregulates the expression of antioxidant enzymes such as CAT and PRDX2 via activation of FoxO3. The results indicate that Resveratrol inhibits AKT resulting in FoxO3 activation with upregulation of cytoprotective systems allowing the erythroid precursors to survive the oxidative damage and proceed with the differentiation. Thus, considering the possibility of using this complementary tool in treating diseases with chronic stress oxidative, such as β-thalassemia [102].

Other pharmaceutical compounds approved for other uses have been shown to activate FoxO3. For example, Bepridil and Trifluoperazine could promote FoxO3 translocation to the nucleus by inhibiting AKT phosphorylation [103]. Metformin is another promising compound. This drug can induce AMPK-mediated phosphorylation and nuclear translocation of FoxO3 [104]. This metformin-induced pathway is also shown to promote Trx transcription (thru activation of FoxO3 and subsequently upregulation of Trx) and thus causes a decrease in ROS levels [105]. Hence, the AMPK-FoxO3-Trx axis may be an essential defense mechanism against excessive ROS production induced by stress and could be a therapeutic target in treating diseases.

As demonstrated in the studies above, FoxO3 plays a central role in antioxidant defense and through its activation by different drugs. Therefore, it is a promising research field for developing new therapeutic strategies to fight chronic oxidative stress in several diseases. Table 1 shows various stress-related disorders and how FoxO3 can be related to the cause or therapeutic target concerning such conditions.

Table 1 Oxidative stress-related diseases and FoxO3’s interactions
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Conclusion

There is considerable interest in understanding the mechanisms underlying the role of oxidative stress not only in disease development but also in life-history trade-offs, as redox signaling and oxidative damage regulate essential physiological functions [11], as stated by the “Redox signaling hypothesis of life history”. Thus, this hypothesis points to the importance of the cell-regulatory systems and how the generation of molecular oxidative damage is the mechanism that drives covariation among life history traits and self-maintenance (reviewed in detail in [158]).

Therefore, despite the challenges and limitations in targeting oxidative stress, the continuous development of this study field is essential to establishing alternative therapeutic strategies that offer meaningful ways to prevent or reduce pathology. One situation in which FoxO3 versatility highlights its importance. Recent research in human health and disease provides new insights into the molecular mechanisms underlying the role and regulation of this essential TF. In addition, comprehending the FoxO3 role as a crucial element in maintaining the equilibrium that supports life will help understand the molecular underpinning of age-associated diseases and maybe lifespan and how to deal with it.

Hence, the continuous search for identifying small pharmaceutical or nutraceutical molecules that directly or indirectly activate FoxO3 is of great interest to the aging and human wellness research field. Thus, the discovery of several other FoxO3 activators and pathways leading to its activation will occur in the coming years, leading to the expected significant development in the therapeutic field, allowing more precise pharmacological intervention with lower risks of side effects. Thus, with continued investment in this research area, the suitable FoxO3 activator for several health issues is expected to reach the general population for prophylactic use in the coming decades [159].

For this to be possible, we reinforce that studies that detail the molecular mechanism of FOXO3 gene expression modulation and its impact are required. The discovery of these action mechanisms can potentially be used in the treatment and management of many diseases, such as diabetes, cancer, neurodegeneration, and heart disease. Lastly, it can help to delay the aging process and minimize the side effects of aging.