Dietary Antioxidants and Redox Signaling in Cancer Prevention: Mechanistic Insights and Metabolic Inflammation

1. Introduction

Oxidative stress reflects a dynamic imbalance between reactive oxygen species (ROS) generation and antioxidant defense systems [1]. Excessive ROS promote DNA damage and tumor initiation [2]. Tightly controlled ROS signaling is essential for physiological cellular processes and immune responses. This dual role underscores that redox homeostasis is not a static equilibrium. It is a finely regulated system that determines whether oxidative signals support adaptation or drive pathological transformation [3]. ROS exert context-dependent effects in carcinogenesis [4]. Multiple factors influence this context, for example, ROS concentration and metabolic state. Moderate and sustained ROS levels activate redox-sensitive signaling pathways such as MAPK/ERK and PI3K/Akt, promoting tumor growth and survival [5,6], whereas excessive ROS accumulation induces oxidative damage and triggers cell death mechanisms, including apoptosis and ferroptosis [7]. Cancer cells adapt to this oxidative environment by upregulating endogenous antioxidant systems, e.g. the Nrf2-Keap1 axis, allowing them to maintain ROS at levels that support proliferation while avoiding cytotoxicity [8]. This adaptive redox regulation represents a critical challenge in developing effective prevention and therapeutic strategies [9]. Dietary antioxidants were considered protective against cancer through their ability to neutralize ROS [10]. This antioxidant paradox highlights the complexity of redox homeostasis [11]. Randomized trials using high-dose isolated antioxidant supplements have reported inconsistent or even adverse outcomes [12]. Dietary antioxidants may influence redox-sensitive signaling pathways beyond direct ROS scavenging [13].

This narrative review aims to integrate current preclinical and clinical evidence on the role of dietary antioxidants related to redox signaling in cancer prevention. We focus on key molecular pathways, metabolic and inflammatory crosstalk, and microbiota-mediated effects, while emphasizing the context-dependent nature of antioxidant interventions and their implications for personalized, evidence-based prevention strategies.

2. Materials and Methods

This narrative review was designed to synthesize evidence on the molecular, metabolic, and translational roles of dietary antioxidants in the modulation of oxidative stress relevant to cancer prevention. The review integrates data from preclinical, mechanistic, translational, and clinical studies. We performed an extensive literature search of Scopus, Web of Science, and PubMed. We focused on articles published between 2021 and 2026. The last search was conducted on 27 March 2026. Earlier seminal studies were also considered in this review. The search was limited to articles published in English. Keywords included ‘’dietary antioxidants’’, ‘’oxidative stress’’, ‘’reactive oxygen species’’, ‘’redox homeostasis’’, ‘’cancer prevention’’, ‘’gut microbiota’’, ‘’Nrf2 signaling’’, ‘’inflammasome’’, and ‘’metabolic inflammation’’. We prioritized studies that provided mechanistic insights, translational relevance, or clinical data regarding antioxidant-rich foods, phytochemicals, whole dietary patterns, and isolated antioxidant supplements in relation to oxidative stress, metabolic regulation, inflammation, and carcinogenesis.

The inclusion criteria were:

1. Human, animal, and experimental studies, as well as narrative, systematic review, or meta-analyses, that evaluated dietary antioxidants, oxidative stress, or redox-related mechanisms relevant to cancer development or prevention.

2. Studies reporting outcomes related to oxidative stress modulation, including reactive oxygen species (ROS) production, antioxidant enzyme activity, redox biomarkers, inflammatory pathways, mitochondrial function, or metabolic alterations associated with carcinogenesis.

3. A particular focus was on studies investigating molecular pathways involved in redox regulation and cancer biology, including Nrf2-Keap1 signaling, AMPK-mTOR pathways, inflammasome activation, autophagy and mitophagy, metabolic inflammation, and the role of dietary phytochemicals or antioxidant-rich dietary patterns in cancer prevention.

We structured the synthesis to describe the molecular mechanisms of oxidative stress modulation, the role of dietary antioxidants and phytochemicals in redox regulation, and the interactions between metabolic, inflammatory, and mitochondrial pathways relevant to cancer prevention. In this review, we also discussed translational perspectives, including dietary patterns, biomarker-guided approaches, and precise nutrition strategies targeting redox homeostasis.

We excluded conference abstracts without full text, letters, case reports without mechanistic discussion, and articles not written in English.

Since this is a narrative review, study selection was based on scientific relevance and conceptual contribution rather than on predefined PICOS criteria. As this is not a systematic review, no formal risk-of-bias or methodological quality assessment was performed.

This narrative review was conducted in accordance with MDPI recommendations for narrative reviews. No PRISMA flow diagram or formal risk-of-bias assessment was applied.

The Materials and Methods should be described with sufficient details to allow others to replicate and build on the published results. Please note that the publication of your manuscript implicates that you must make all materials, data, computer code, and protocols associated with the publication available to readers. Please disclose at the submission stage any restrictions on the availability of materials or information. New methods and protocols should be described in detail while well-established methods can be briefly described and appropriately cited.

Research manuscripts reporting large datasets that are deposited in a publicly available database should specify where the data have been deposited and provide the relevant accession numbers. If the accession numbers have not yet been obtained at the time of submission, please state that they will be provided during review. They must be provided prior to publication.

Interventionary studies involving animals or humans, and other studies require that ethical approval, must list the authority that provided approval and the corresponding ethical approval code.

3. Redox Homeostasis and Reactive Oxygen Species (ROS) Signaling in Cancer Development

3.1. Oxidative Stress as a Contemporary Concept in Cancer Prevention

Reactive oxygen species (ROS) exert paradoxical roles in cancer. At moderately elevated levels, they promote tumor growth and angiogenesis through activation of redox-sensitive signaling pathways [14]. When ROS levels exceed antioxidant defenses, they cause cytotoxic damage and trigger cell death [7]. Cancer cells adapt their antioxidant defenses in order to survive chronic oxidative stress [9]. At the same time, they exploit ROS to support invasion and metastasis. Redox homeostasis represents an important determinant at every stage of tumorigenesis [15].

ROS can activate important signaling pathways, including MAPK/ERK and PI3K/Akt, to support cellular proliferation [16]. Excessive ROS can induce oxidative damage to proteins, nucleic acids, and also lipids, when antioxidant defenses are overwhelmed [17].

Antioxidant supplementation may also exert context-dependent effects in cancer [14]. In certain oncogene-driven tumors, antioxidant supplementation can promote tumor progression [18]. For example, in KRAS-driven lung cancer, antioxidant supplementation may accelerate tumor progression [19], while in BRAF-driven melanoma, they accelerate metastasis by reducing oxidative stress [20].

High ROS levels trigger genomic instability through mutagenic DNA lesions such as 8-oxo-dG [17]. ROS also promote epithelial-to-mesenchymal transition (EMT). This mechanism underlies metastatic spread [15].

Oxidative stress is associated with cancer hallmarks by driving metabolic reprogramming [21] and chronic inflammation [22]. This altered redox homeostasis creates vulnerabilities in tumor cells that can be therapeutically exploited [14]. Excessive ROS induce oxidative cell death pathways, including ferroptosis and pyroptosis [7].

3.2. Physiological ROS Signaling versus Pathological Oxidative Stress

At normal physiological levels, ROS are necessary for many cellular processes. This state is called "oxidative eustress". These molecules include free radicals (e.g., superoxide anion) and non-radicals (e.g., hydrogen peroxide). Signaling mainly occurs through redox switches. This regulates important pathways. These pathways control cell cycle regulation, differentiation, proliferation, and immune responses. Maintaining redox homeostasis is a dynamic challenge, often described as "homeodynamics" [3].

Spatiotemporal control of ROS is important for maintaining redox homeostasis. Hydrogen peroxide (H₂O₂) concentrations differ by orders of magnitude between organelles. Redox signaling follows principles that regulate spatiotemporal dynamics of cellular processes. Specific aquaporins facilitate H₂O₂ transmembrane diffusion, enabling its function as a controlled intracellular messenger [16].

When ROS generation exceeds antioxidant defenses, "oxidative distress" occurs. This imbalance causes severe oxidative damage to proteins, lipids, and nucleic acids, leading to cell death through apoptosis or necrosis [23].

At low to moderate levels, ROS stimulate tumorigenesis by inducing genetic mutations and promoting proliferation through signaling pathways [15]. Cancer cells often amplify their antioxidant systems, such as the Nrf2 pathway, to limit ROS to levels that promote growth while avoiding cytotoxicity [24]. Metabolic reprogramming, including the Warburg effect, contributes to redox homeostasis by modulating mitochondrial function and ROS production [25].

Figure 1. Dietary antioxidants and redox signaling in cancer prevention. Created with BioRender

Dietary antioxidants and phytochemicals modulate redox homeostasis through multiple molecular pathways, including Nrf2-Keap1 signaling, AMPK-mTORC1 regulation, NF-κB-mediated inflammation, and MAPK pathways. These coordinated mechanisms support mitochondrial quality control, autophagy, and NLRP3 inflammasome regulation, ultimately contributing to cellular homeostasis and cancer risk modulation.

Abbreviations: AMPK, AMP-activated protein kinase; ARE, antioxidant response element; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; MAPK, mitogen-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain-containing 3; NOD, nucleotide-binding oligomerization domain, Nrf2, nuclear factor erythroid 2–related factor 2; ROS, reactive oxygen species; SCFA, short-chain fatty acids.

3.3. Inflammasome–ROS Crosstalk in Cancer Prevention

Inflammasomes are multiprotein complexes that detect cellular danger signals and regulate immune and inflammatory responses. The interaction between inflammasomes and ROS is bidirectional and context-dependent, contributing to both tumor-promoting and tumor-suppressive effects [26]. The NLRP3 inflammasome is the most studied member of the NLR family. It requires a two-step activation mechanism [27]. First, a 'priming' signal induces the expression of inflammasome components through NF-κB activation. Then, an activating signal triggers assembly of the protein complex. Mitochondrial ROS acts as an activator signal, linking oxidative stress to inflammatory responses [28].

In normal cells and early malignant transformation, inflammasome activation facilitates elimination of damaged cells through pyroptosis [27]. This process limits the accumulation of oncogenic mutations and contributes to immune surveillance and tissue homeostasis [29]. Experimental studies show that inflammasome deficiency increases cancer susceptibility in multiple animal models [30].

Chronic inflammasome-mediated inflammation can create a tumor microenvironment that favors cancer progression [29]. This process influences multiple stages of tumor development. Persistent activation of NLRP3 inflammasome leads to the release of pro-inflammatory cytokines, e.g. IL-1β and IL-18 [27]. These cytokines promote tumor angiogenesis and extracellular matrix remodeling. It also recruits the myeloid-derived suppressor cells (MDSCs) [29]. This dual role illustrates how timing and cellular environment determine the function of the inflammasome in cancer.

Multiple control mechanisms, for example mitochondrial autophagy (mitophagy) and endogenous antioxidant systems, regulate the interaction between ROS and inflammasomes [31]. IL-10, an anti-inflammatory cytokine, inhibits NLRP3 inflammasome activation in macrophages [29]. These regulatory processes suggest that modulation of redox balance could influence inflammasome activity and the antitumor immune response.

Dietary antioxidants can modulate inflammasome activation through several mechanisms. These include the regulation of mitochondrial ROS and the modulation of inflammatory gene expression through Nrf2 signaling [32]. They also influence macrophage polarization toward pro- or anti-inflammatory phenotypes. The Dietary Antioxidant Index (DAI) quantifies the intake of vitamins A, C, E and minerals such as zinc and selenium. Studies show an inverse association between DAI and chronic diseases, including cancer [33].

At physiological concentrations (50-200 µM), vitamin C functions as a conventional antioxidant, neutralizing ROS and maintaining redox balance. In contrast, pharmacological doses (milimolar range) can exert pro-oxidant effects by generating ascorbate radical and hydrogen peroxide (H₂O₂) in the extracellular environment [34]. This shift in redox activity may contribute to cytotoxic effects in certain tumor contexts. These dose-dependent dual effects highlight the need for precise titration of antioxidant interventions.

4. Conceptual Framework

4.1. The Antioxidant Paradox in Cancer Prevention

The relationship between antioxidants and cancer prevention is often seen as a paradox [18]. This paradox arises from the dual nature of reactive oxygen species (ROS) [35]. Klein et al. (2011) reported that large-scale intervention studies, including the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Selenium and Vitamin E Cancer Prevention Trial (SELECT), demonstrated a lack of protective effect of antioxidant supplementation. In some cases, increased cancer incidence was reported among participants receiving antioxidant supplements [36,37]. These results reshaped current understanding of the role of oxidative stress in cancer.

Dietary patterns rich in antioxidants, such as the Mediterranean diet, were associated with lower cancer risk in epidemiological studies [38]. These findings suggest that protective effects arise from interactions between many bioactive compounds, fiber, and other dietary components rather than from individual antioxidants alone.

4.2. Thresholds for Adaptive Signaling and Redox Hormesis

The concept of hormesis provides a framework for understanding the complex relationship between ROS and cellular health. It represents an adaptive response that enhances cellular resilience and protects against subsequent oxidative damage [39].

Mitohormesis is a specific form of redox hormesis involving mitochondria. It occurs when mild mitochondrial stress triggers adaptive responses. In mitohormesis, transient mitochondrial ROS production activates signaling pathways that increase cellular resistance to future metabolic and oxidative stress. Exercise induces transient increases in mitochondrial ROS production, which act as signaling molecules to promote adaptive cellular responses [40].

Conversely, excessive reduction of ROS levels in cancer cells through antioxidant supplementation may create conditions that favor tumor survival and growth, potentially enhancing tumor progression [18].

5. Mechanism-Based Classification of Dietary Antioxidants

Dietary antioxidants primarily modulate redox signaling [41].

Table 1. Major redox-sensitive molecular pathways and dietary antioxidants.

Molecular pathway / mechanism	Main role in redox regulation and cancer prevention	Representative dietary modulators / examples	Cancer prevention relevance	References
Redox hormesis / mitohormesis	Moderate ROS signaling activates adaptive stress responses.	Mild mitochondrial stress, exercise; antioxidant supplementation may interfere.	Explains why low-to-moderate oxidative signaling may be beneficial.	[18,39,40]
Nrf2-Keap1-ARE axis	Activates cytoprotective antioxidant and detoxification programs.	Sulforaphane, resveratrol, curcumin, electrophilic phytochemicals.	Limits oxidative damage in early carcinogenesis but may support tumor adaptation when persistently activated.	[32,42,43]
AMPK-mTOR-IGF-1 signaling	Links energy sensing with redox balance and metabolic adaptation.	Polyphenols, nutrient availability, metabolic status.	Supports metabolic resilience but may be exploited by established tumors.	[44,45,46]
NF-κB redox-sensitive inflammatory signaling	Connects ROS with inflammatory signaling.	Curcumin, quercetin, antioxidant-rich dietary patterns.	Links oxidative stress to chronic inflammation, invasion, and immune evasion.	[22,47,48,49]
Autophagy and mitophagy / mitochondrial quality control	Removes damaged ROS-producing mitochondria.	Indirectly influenced by redox-modulating compounds and nutrient-sensing pathways.	Protects mitochondrial integrity early, but may later support tumor survival.	[31,50,51,52]
NLRP3 inflammasome and reactive oxygen species crosstalk	Links redox stress with inflammasome activation and inflammatory signaling.	Dietary antioxidants, phytochemicals, vitamin C.	Supports immune surveillance early, but chronic activation may promote tumor progression.	[26,27,28,31,53,54]

Abbreviations: AMPK, AMP-activated protein kinase; ARE, antioxidant response element; IGF-1, insulin-like growth factor 1; Keap1, Kelch-like ECH-associated protein 1; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain-containing 3; ROS, reactive oxygen species.

Table 1. Major redox-sensitive molecular pathways and dietary antioxidants.

Molecular pathway / mechanism	Main role in redox regulation and cancer prevention	Representative dietary modulators / examples	Cancer prevention relevance	References
Redox hormesis / mitohormesis	Moderate ROS signaling activates adaptive stress responses.	Mild mitochondrial stress, exercise; antioxidant supplementation may interfere.	Explains why low-to-moderate oxidative signaling may be beneficial.	[18,39,40]
Nrf2-Keap1-ARE axis	Activates cytoprotective antioxidant and detoxification programs.	Sulforaphane, resveratrol, curcumin, electrophilic phytochemicals.	Limits oxidative damage in early carcinogenesis but may support tumor adaptation when persistently activated.	[32,42,43]
AMPK-mTOR-IGF-1 signaling	Links energy sensing with redox balance and metabolic adaptation.	Polyphenols, nutrient availability, metabolic status.	Supports metabolic resilience but may be exploited by established tumors.	[44,45,46]
NF-κB redox-sensitive inflammatory signaling	Connects ROS with inflammatory signaling.	Curcumin, quercetin, antioxidant-rich dietary patterns.	Links oxidative stress to chronic inflammation, invasion, and immune evasion.	[22,47,48,49]
Autophagy and mitophagy / mitochondrial quality control	Removes damaged ROS-producing mitochondria.	Indirectly influenced by redox-modulating compounds and nutrient-sensing pathways.	Protects mitochondrial integrity early, but may later support tumor survival.	[31,50,51,52]
NLRP3 inflammasome and reactive oxygen species crosstalk	Links redox stress with inflammasome activation and inflammatory signaling.	Dietary antioxidants, phytochemicals, vitamin C.	Supports immune surveillance early, but chronic activation may promote tumor progression.	[26,27,28,31,53,54]

Abbreviations: AMPK, AMP-activated protein kinase; ARE, antioxidant response element; IGF-1, insulin-like growth factor 1; Keap1, Kelch-like ECH-associated protein 1; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain-containing 3; ROS, reactive oxygen species.

5.1. Polyphenols

Polyphenols can regulate molecular signaling pathways and epigenetic mechanisms [55].

Sulforaphane, resveratrol, and curcumin activate the Nrf2 transcription factor [24]. Stabilized Nrf2 moves to the nucleus and binds Antioxidant Response Elements (ARE), inducing the expression of cytoprotective genes such as HO-1, NQO-1, SOD and catalase that neutralize reactive oxygen species and prevent oxidative damage [34].

Polyphenols inhibit the NF-κB pathway, which is chronically activated during aging [48]. This decreases pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, thereby limiting persistent inflammation. Polyphenols also activate AMP-activated protein kinase (AMPK), involved in the regulation of cellular metabolism. AMPK activation is associated with improved mitochondrial function, enhanced autophagy, and broader redox-adaptive signaling responses [41].

Polyphenols can modulate gene expression using epigenetic mechanisms [56]. They can inhibit DNA methyltransferases (DNMTs), reversing aberrant methylation of promoter regions, including Nrf2 gene, to restore antioxidant gene expression [57]. Many polyphenols also inhibit histone deacetylases (HDACs), promoting histone acetylation and chromatin relaxation, and prevent transcriptional repression of tumor suppressor and anti-inflammatory genes [55].

5.2. Carotenoids

High dietary intake of carotenoids from fruits and vegetables links to lower cancer risk, including breast cancer [58].

Large, randomized trials, including the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Beta-Carotene and Retinol Efficacy Trial (CARET) were terminated early because high-dose β-carotene increased incidence of lung cancer and mortality in smokers [36,37]. Lifestyle-based approaches support that the protective effects of antioxidants are more pronounced when derived from whole dietary patterns rather than isolated supplementation [59].

Under conditions of elevated oxidative stress or at high concentrations, carotenoids can shift from protective antioxidants to pro-oxidant activity [60]. This context-dependent behavior explains why dietary carotenoids are beneficial, whereas high-dose supplementation can be harmful in certain populations.

5.3. Organosulfur Compounds and Electrophilic Phytochemicals

Keap1 functions as a redox sensor that regulates the activation of cytoprotective pathways. Its cysteine residues detect oxidative stress and promote NRF2 activation, thereby inducing phase II detoxifying enzymes. These enzymes protect cells against carcinogens and harmful oxidants [42]. Sulforaphane (SFN), a bioactive compound from cruciferous vegetables, modulates cell survival pathways. SFN activates the Nrf2 signaling pathway, which enhances cellular antioxidant defenses [61].

Garlic compounds, such as diallyl disulfide (DADS) and diallyl trisulfide (DATS), exert anticancer effects through multiple molecular mechanisms, including induction of apoptosis and inhibition of cell proliferation [62].

5.4. Vitamins with Antioxidant Properties (C and E)

Isolated antioxidant vitamin supplementation produced inconsistent and, in some cases, adverse outcomes in cancer prevention. High-dose vitamin E and C supplements have not demonstrated protective effects against tumor development [63]. In some studies, antioxidant supplementation was associated with an increased incidence of cancer. Large clinical trials report heterogeneous findings. The SELECT trial ended early when vitamin E raised prostate cancer risk [36].

Vitamin C exhibits dose-dependent biological effects. Oral supplementation is limited by intestinal absorption and homeostatic control of plasma levels. Supplements may be beneficial in patients with documented deficiencies. In individuals with adequate baseline levels, supplementation has shown no clear benefit and may even be harmful. Intravenous administration achieves millimolar plasma concentrations and exerts pro-oxidant cytotoxic effects in tumor cells. Chronic high-dose oral vitamin C may increase oxalate production and was associated with an increased risk of kidney stone formation in some populations [34]. Current evidence supports prioritizing prevention of deficiencies through diet rather than routine high-dose supplementation [59].

6. Molecular Mechanisms of Oxidative Stress Modulation

6.1. Nrf2-Keap1-ARE Axis

The Nrf2-Keap1-ARE axis is a major pathway that regulates the cellular response to oxidative stress. Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1, which facilitates proteasomal degradation [43]. Under conditions of cellular stress or exposure to reactive species, Keap1 undergoes conformational modifications that lead to the release and stabilization of Nrf2. Stabilized Nrf2 accumulates in the cell and translocates to the nucleus. Once Nrf2 enters the nucleus, it binds to antioxidant response elements (ARE) located in the promoter regions of specific target genes. This binding initiates the transcription of cytoprotective genes involved in antioxidant defense and detoxification. This mechanism allows cells to respond to stress while maintaining a balanced redox state, rather than eliminating ROS. Once activated, Nrf2 induces an antioxidant network that includes phase II detoxification enzymes along with the glutathione and thioredoxin systems [32].

Phase II detoxifying enzymes contribute to neutralization of harmful compounds and facilitate their elimination, while glutathione and thioredoxin systems maintain intracellular redox homeostasis. At the same time, these systems do not eliminate ROS. Instead, they restore the redox balance, which allows normal signaling to continue. This regulation of oxidative stress is an important mechanism through which dietary antioxidants and cellular defense systems maintain homeostasis [43].

In normal cells, during the early stages of carcinogenesis, Nrf2 protects cells by activating antioxidant defenses and facilitating the detoxification of carcinogens [42]. Nrf2 limits DNA damage and prevents the initiation of malignant transformation. In established tumors, persistent activation of Nrf2 may contribute to cancer progression. Genetic alterations in KEAP1, NFE2L2, or related pathways can lead to continuous Nrf2 activation, which enables cancer cells to maintain stronger antioxidant defenses, resist treatment, and adapt to metabolic stress [32].

Nrf2 is often called a “double-edged sword,” since it protects cells at early stages but can promote tumor growth in advanced cancer [64].

6.2. AMPK-mTOR-IGF-1 Signaling

The AMPK-mTOR-IGF-1 axis links cellular energy sensing with redox and oxidative stress control [44]. AMPK is activated by elevated AMP/ATP ratios and functions as a sensor of cellular energy status. Concurrently, AMPK enhances antioxidant defenses through NAD⁺-dependent activation of the SIRT1/PGC-1α–FoxO pathway, enhancing the expression of antioxidant enzymes like superoxide dismutases (SODs) and catalase. This shift from anabolic activity to stress adaptation helps cells maintain redox balance when nutrients are limited or when the cell is under oxidative stress [41]. Upon activation, AMPK suppresses anabolic pathways by inhibiting mTORC1, conserving energy [44] and modulating metabolic processes associated with ROS production [25].

In contrast, mTORC1 and IGF-1 signaling support anabolic growth under nutrient-rich conditions and actively regulate cellular redox [46]. IGF-1 signaling is also implicated in antioxidant protection and redox regulation [65]. These mechanisms help to limit intracellular hydrogen peroxide accumulation. Even though this balance supports normal tissue growth, persistent activation of the PI3K-AKT-mTOR pathway can disturb the redox homeostasis. This disturbance increases oxidative stress, which may cause cell damage and dysfunction. This effect is often seen in hyperinsulinemia and metabolic syndrome. When this pathway is disrupted, redox imbalance may contribute to insulin resistance and the development of cancer. Long-term oxidative stress activates inhibitory enzymes like PTEN and PTP1B, which impair IGF-1 and insulin signaling contributing to metabolic dysfunction [41].

Reduced AMPK activity in obesity and diabetes fails to restrain mTORC1, thereby enhancing anabolic signaling and promoting mitochondrial dysfunction. In cancer, this signaling network plays context-dependent roles. AMPK can function as a tumor suppressor by restraining mTOR-driven biosynthesis and metabolic reprogramming [44]. Established tumors exploit AMPK-mediated metabolic adaptation and redox buffering to survive hypoxia, nutrient deprivation, and therapy-induced oxidative stress. Collectively, the AMPK-mTOR-IGF-1 axis links metabolic stress to redox control and cancer progression [66].

6.3. NF-κB and Redox-Sensitive Inflammatory Signaling

NF-κB functions as a key redox-sensitive transcription factor that couples oxidative stress to inflammatory signaling [49]. Reactive oxygen species (ROS) regulate multiple steps of the IKK-IκB-NF-κB cascade in a context-dependent manner: low-to-moderate levels promote pathway activation, whereas excessive ROS impair signaling through oxidative modification of pathway proteins [66]. Upon activation, NF-κB induces pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β and can also enhance the production of ROS-generating enzymes. This creates a self-amplifying inflammatory loop that reinforces redox imbalance and sustains chronic inflammatory signaling [47].

Within the tumor microenvironment, hypoxic and metabolically stressed conditions elevate mitochondrial and NOX-derived ROS production [66], promoting persistent NF-κB activation across both tumor and stromal compartments [11]. This redox-driven signaling reprograms tumor-associated macrophages toward an immunosuppressive state and activates cancer-associated fibroblasts through NOX4-TGF-β, amplifying inflammatory and oxidative cues [15]. The resulting inflammatory environment advances angiogenesis, invasion, immune evasion, and therapy resistance. This makes ROS-dependent NF-κB signaling a key driver of tumor-promoting inflammation in stressed cells [66].

6.4. Autophagy and Mitophagy as Redox Quality-Control Mechanisms

Autophagy and mitophagy act as central redox quality-control mechanisms by selectively eliminating damaged, ROS-producing mitochondria, therefore preserving mitochondrial network integrity [51]. This process limits oxidative damage to cellular macromolecules [50]. Redox stress engages autophagy and mitophagy via AMPK-mTOR-ULK1 signaling pathways [67]. In parallel, it induces mitophagy via stabilization of PINK1 on depolarized mitochondria, which recruits Parkin for clearance of damaged organelles [52].

Impaired function of mitophagy regulators, such as PINK1, Parkin, and BNIP3, leads to increased oxidative stress, promoting a shift toward glycolytic metabolism [51]. These alterations may contribute to cellular transformation and tumor progression. In established tumors, these quality-control processes are co-opted to support survival under hypoxia and nutrient deprivation. Autophagy and mitophagy exhibit stage-dependent dual roles in carcinogenesis, suppressing tumor initiation early while supporting metabolic adaptation and stress tolerance in advanced disease [50].

7. Inflammasome Activation as a Redox-Sensitive Link Between Oxidative Stress, Metabolism, and Cancer Risk

7.1. ROS as Upstream Activators of Inflammasomes

Mitochondrial reactive oxygen species (mtROS) act as early danger signals, linking mitochondrial damage to the activation of the NLRP3 inflammasome. This mechanism represents a pathway through which mitochondrial dysfunction promotes inflammasome assembly and inflammatory signaling. Excess mtROS promotes opening of the mitochondrial permeability transition pore (mPTP) and voltage-dependent anion channel (VDAC) oligomerization, enabling cytosolic release of oxidized mitochondrial DNA. The mitochondrial DNA serves as a damage-associated molecular pattern that directly engages and activates NLRP3 inflammasome [68].

In addition to acute activation, ongoing chronic low-grade oxidative stress sustains a basal level of activity of the NLRP3 inflammasome, promoting a persistent pro-inflammatory state linked to cancer risk and prevention [69]. ROS contribute to both inflammasome priming and activation. Mitochondrial reactive oxygen species and cytosolic mitochondrial DNA promote NF-κB activation through cGAS-STING pathway to upregulate NLRP3 and pro-IL-1β [68]. At the same time, ongoing mitochondrial damage provides the second signal required for inflammasome assembly [28]. Continuous NLRP3 signaling advances a pro-tumorigenic microenvironment by increasing the production of inflammatory cytokines and angiogenic factors [69]. It also drives immunosuppressive programs and promotes epithelial transformation and tumor progression under chronic oxidative stress [53].

7.2. NLRP3 Inflammasome, Metabolic Inflammation, and Redox-Regulated Carcinogenesis

Metabolic inflammation associated with obesity and insulin resistance creates a chronic inflammatory environment for NLRP3 inflammasome activation, linked to increased cancer risk. NLRP3-mediated IL-1β impairs insulin signaling and reinforces metabolic dysfunction. Hypoxia amplifies inflammasome activation via HIF-1α-mediated metabolic reprogramming and ATP release. These mechanisms sustain low-grade systemic inflammation (”metaflammation”), promoting early carcinogenesis [54].

Lipotoxic mediators activate TLR4-NF-κB signaling and increase mitochondrial ROS. Macrophage-driven feedback loops sustain chronic inflammation [70].

Autophagy and mitophagy act as counter-regulatory mechanisms. These processes limit the accumulation of mitochondrial ROS and damage-associated molecular patterns [31]. Efficient mitophagy prevents excessive inflammasome activation and preserves cellular homeostasis [26].

Dietary antioxidants and phytochemicals may modulate NLRP3 inflammasome activity through upstream redox and mitochondrial pathways involved in priming and assembly [48].

Polyphenols like curcumin and quercetin suppress NF-κB priming and reduce expression of NLRP3 and pro-IL-1β levels. Other compounds, such as resveratrol, interfere with mitochondrial dynamics and endoplasmic reticulum-mitochondria contact sites, which are required for inflammasome assembly [48].

8. Gut Microbiota as a Mediator of Antioxidant Bioactivity

8.1. Parent Compounds versus Microbial Metabolites

The bioavailability and systemic efficacy of dietary polyphenols depend on colonic biotransformation by gut microbiota. Only 5–10% of ingested polyphenols are absorbed in the small intestine as free compounds. 90–95% reach the colon where resident microbes catalyze extensive structural modifications [71]. These transformations involve deglycosylation, C-ring cleavage, dehydroxylation, demethylation, and hydrogenation [72]. Mammalian enzymes lack the capacity to cleave the core flavonoid ring system, rendering microbial catabolism indispensable for enabling their biological activity [73].

Specific bacterial taxa orchestrate class-dependent transformations. Quercetin undergoes sequential deglycosylation and ring fission by Eubacterium ramulus and Clostridium orbiscindens, producing 3,4-dihydroxyphenylacetic acid and protocatechuic acid. These metabolites exhibit potent anti-inflammatory, neuroprotective, and insulin-sensitizing activities superior to the parent flavonol [74]. Similarly, daidzein is converted through a four-step enzymatic cascade by Slackia isoflavoniconvertens and Adlercreutzia equolifaciens into (S)-equol, an estrogenic metabolite with enhanced cardiovascular and bone-protective effects [73]. Ellagitannins, poorly absorbed in their native form, are hydrolyzed to ellagic acid and subsequently transformed by Gordonibacter and Ellagibacter species into urolithins, particularly urolithin A [75].

The superior bioactivity of microbial metabolites extends to resveratrol, whose gut-derived dihydroresveratrol exhibits greater tissue retention and anti-proliferative capacity than resveratrol itself. Catechin- and anthocyanin-derived microbial metabolites modulate metabolic signaling by activating SIRT-1-mediated autophagy and improving insulin sensitivity [76,77]. Fermentation-induced deglycosylation exposes additional phenolic hydroxyl groups, enhancing radical scavenging capacity and lipid peroxidation inhibition beyond that of unfermented precursors [78]. These findings underscore that the health benefits traditionally attributed to polyphenol-rich foods are mediated predominantly by microbially generated metabolites. Inter-individual variability in microbiota composition may determine metabolic phenotypes and therapeutic responses [71].

8.2. Intestinal Barrier Integrity and Ahr–Nrf2 Signaling

Microbiota-derived polyphenol metabolites exert protective effects on intestinal epithelial integrity through modulation of tight junction architecture and redox-sensitive signaling pathways. These mechanisms reduce paracellular permeability and prevent translocation of bacterial lipopolysaccharides (LPS) into systemic circulation [71]. Fermentation-enhanced phenolic content supports barrier integrity and helps prevent oxidative stress in the intestinal mucosa. This may contribute to intestinal homeostasis and reduce the risk of inflammatory bowel disease and metabolic endotoxemia [78].

Short-chain fatty acid (SCFA) metabolites suppress pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6). Anti-inflammatory mediators such as IL-10 are also stimulated, contributing to cytokine modulation in colonic tissues. Production of short-chain fatty acids (SCFAs) by commensal bacteria may further support intestinal homeostasis and redox-sensitive immune regulation [71].

9. Dietary Patterns and Translation to Cancer Prevention

9.1. Mediterranean and Plant-Forward Dietary Patterns

Accumulating evidence from large-scale prospective cohorts demonstrates that adherence to Mediterranean and plant-forward dietary patterns confers modest but consistent reductions in cancer incidence and mortality. In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort of approximately 520,000 participants followed for a median of 8.7 years, each two-point increment in Mediterranean diet score was associated with a 4% reduction in overall cancer risk (HR = 0.96, 95% CI 0.95–0.98), with similar effects observed in men and women [38]. Population-level modeling suggested that 4.7% of cancers in men and 2.4% in women could be avoided if adherence shifted to the highest category. Meta-analytic syntheses corroborate these findings, reporting a 13% reduction in cancer mortality among the general population (RR = 0.87, 95% CI 0.82–0.92) and a 25% reduction in all-cause mortality among cancer survivors (RR = 0.75, 95% CI 0.66–0.86) with highest Mediterranean diet adherence [11].

Site-specific analyses reveal heterogeneous effects across cancer types. The strongest inverse associations emerge for gastrointestinal malignancies, including colorectal cancer (RR = 0.83, 95% CI 0.76–0.90), gastric cancer (RR = 0.70, 95% CI 0.61–0.80), and liver cancer (RR = 0.64, 95% CI 0.54–0.75), alongside head and neck cancers (RR = 0.56, 95% CI 0.44–0.72) [11]. Plant-based dietary patterns demonstrate comparable protective effects, with overall plant-based diet indices associated with 12% lower cancer mortality (RR = 0.88, 95% CI 0.79–0.98) and healthy plant-based indices showing 9% reductions (RR = 0.91, 95% CI 0.83–0.99), whereas unhealthy plant-based patterns characterized by refined grains and added sugars show null or adverse associations [79].

Several methodological limitations constrain causal inference. The proliferation of distinct Mediterranean diet scoring systems introduces substantial heterogeneity, with median intake thresholds varying markedly across populations [11]. Geographic concentration of evidence in European and North American populations limits generalizability to Asian and other populations with distinct dietary patterns and genetic backgrounds.

9.2. Whole Foods versus Supplements: Risk Stratification

The health benefits associated with Mediterranean and plant-forward dietary patterns appear to arise from synergistic interactions between various bioactive components rather than the effects of singular nutrients. Component analyses from the EPIC cohort demonstrate that no single food group predominates; sensitivity analyses eliminating individual components sequentially, including alcohol, failed to identify a dominant component. Modest independent associations emerged for fruits and nuts (HR = 0.98 per 200g), vegetables (HR = 0.97 per 145g), cereals (HR = 0.97 per 110g), and unsaturated-to-saturated lipid ratios (HR = 0.98 per 0.5-unit increment), suggesting additive rather than singular effects [38].

Baseline diet quality is an important determinant of cancer outcomes. Healthy plant-based patterns emphasizing whole grains, vegetables, and legumes reduce ovarian cancer risk (OR = 0.67, 95% CI 0.53-0.84), whereas unhealthy habits favoring refined carbohydrates and added sugars increase risk (OR = 1.78, 95% CI 1.40-2.28) [80]. Occupational exposures were not systematically examined as effect modifiers in the reviewed literature, representing a gap in risk stratification frameworks.

10. Research Gaps and Methodological Considerations

Several critical research gaps limit current understanding of dietary antioxidants in cancer prevention. We identified three main gaps in the current evidence.

1. The role of mitophagy in mediating the chemoprotective effects of dietary antioxidants is still insufficiently understood.

2. Experimental evidence supporting mitohormesis as a mechanism of dietary antioxidants remain limited

3. The influence of gut microbiota metabolism on the bioactivity of dietary antioxidants is not fully clarified

Methodological considerations for future research include the need for physiologically relevant doses and delivery methods, adequate study duration to capture long-term adaptive responses, incorporation of mechanistic biomarkers alongside clinical endpoints, and attention to food matrix effects. Combinatorial approaches testing whole dietary patterns or synergistic combinations of bioactive compounds may prove more successful than single-compound interventions.

4. Discussion

The role of oxidative stress in cancer prevention is more complex than the traditional view. Reactive oxygen species can promote either physiological adaptation or cellular damage, depending on dose, timing, localization, and metabolic context. This complexity helps explain why antioxidant strategies have produced mixed results across different stages of carcinogenesis.

The contrast between whole-food dietary patterns and isolated antioxidant supplementation further underscores this difference. Diets rich in fruits, vegetables, legumes, whole grains, and other plant-derived foods are generally associated with lower cancer risk. High-dose supplementation with isolated antioxidants has not consistently shown protective effects. In some trials, isolated antioxidant supplements were associated with harm. ATBC, CARET, and SELECT findings suggest that antioxidant supplementation cannot reproduce the complex biological effects of a whole diet. This reflects the importance of food matrix effects, synergistic interactions among bioactive compounds, and differences in baseline redox and metabolic status.

Another important insight from the current literature is that oxidative stress is closely integrated with inflammation, mitochondrial quality control, nutrient sensing, and gut microbiota metabolism. Pathways such as NRF2-KEAP1, AMP-activated protein kinase–mechanistic target of rapamycin signaling, nuclear factor kappa B activation, autophagy, mitophagy, and inflammasome regulation do not operate in isolation. Rather, they form an interconnected network that determines whether oxidative signals promote adaptation or contribute to disease. Dietary antioxidants appear to act mainly by modulating this network, instead of simply scavenging reactive oxygen species.

These observations have practical implications for cancer prevention. Strategies that support mitochondrial function and redox homeostasis are likely to be more effective than indiscriminate suppression of oxidative processes. Regular consumption of minimally processed plant foods and attention to metabolic health is more relevant than routine use of high-dose antioxidant supplements. Supplementation may still have a role in selected settings, particularly in individuals with documented deficiencies, but it should not be assumed to be broadly protective.

At the same time, the field still faces important limitations. Individual responses to dietary antioxidants are shaped by baseline diet quality, metabolic status, inflammation, gut microbiota composition, and possibly occupational or environmental exposures. These variables are rarely integrated into current prevention models. A more precise understanding of redox biology will therefore require biomarker-guided approaches capable of identifying when antioxidant interventions are beneficial, neutral, or potentially harmful.

Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.

5. Conclusions

Dietary antioxidants should be understood within the broader context of redox homeostasis. Factors such as dose, source, metabolic status, and disease stage influence their effects. ROS exert their effects through interactions with endogenous antioxidant systems, inflammatory pathways, and cellular metabolism.

The association between plant-rich dietary patterns and reduced cancer risk contrasts with the inconsistent outcomes of high-dose antioxidant supplementation. The effects of dietary antioxidants depend on biological context. These findings support a shift from isolated nutrient-based approaches toward whole-diet strategies.

In conditions like obesity and insulin resistance, redox signaling intersects with processes including mitochondrial function and inflammasome activation. The gut microbiota transforms dietary compounds into bioactive metabolites. This mechanism may explain the inter-individual variability in response.

Future research should prioritize the identification of reliable biomarkers of redox status, clarification of dose–response relationships, and stratification of populations most likely to benefit from specific interventions. Mechanism-based and personalized approaches will be essential for translating redox modulation into effective cancer prevention strategies.

In conclusion, it is essential to maintain redox homeostasis in a way that preserves physiological signaling while limiting chronic damage.