Therapeutic Strategies Targeting Oxidative Stress and Inflammation: A Narrative Review

Abstract

Oxidative stress and inflammation are deeply interconnected processes implicated in the onset and progression of numerous chronic diseases. Despite promising mechanistic insights, conventional antioxidant and anti-inflammatory therapies such as NSAIDs, corticosteroids, and dietary antioxidants have shown limited and inconsistent success in long-term clinical applications due to challenges with efficacy, safety, and bioavailability. This review explores the molecular interplay between redox imbalance and inflammatory signaling and highlights why conventional therapeutic translation has often been inconsistent. It further examines emerging strategies that aim to overcome these limitations, including mitochondrial-targeted antioxidants, Nrf2 activators, immunometabolic modulators, redox enzyme mimetics, and advanced delivery platforms such as nanoparticle-enabled delivery. Natural polyphenols, nutraceuticals, and regenerative approaches, including stem cell-derived exosomes, are also considered for their dual anti-inflammatory and antioxidant potential. By integrating recent preclinical and clinical evidence, this review underscores the need for multimodal, personalized interventions that target the redox-inflammatory axis more precisely. These advances offer renewed promise for addressing complex diseases rooted in chronic inflammation and oxidative stress.

1. Introduction

The fundamental biological processes of oxidative stress and inflammation perform vital roles in protecting cellular integrity while coordinating responses to injury, infection, and environmental stress. Reactive oxygen species (ROS), normal byproducts of metabolism, can accumulate into excessive amounts that create significant oxidative damage to cellular lipids, proteins, and DNA [1]. Oxidative stress describes a state of the cell characterized by overaccumulation of ROS beyond the body’s antioxidant defense capacity [2]. While ROS is important for cellular redox homeostasis under basal conditions, excessive ROS disrupts normal redox sensitive cellular processes, which results in genetic mutations, protein misfolding, and altered cell signaling mechanisms that produce chronic diseases such as cancer, cardiovascular, and neurodegenerative pathologies [3].

Conversely, the human immune system utilizes inflammation as a protective mechanism to eliminate harmful substances while starting repair processes [4]. The body controls acute inflammation within its natural limits, resolving once the injury or infection clears. However, multiple diseases develop from the pathological combination of chronic and dysregulated inflammation which generates pro-inflammatory cytokines and ROS [5]. The immune system maintains a state of constant activation at low levels to produce chronic inflammation that results from multiple factors including obesity, environmental toxins, inactive lifestyle, and poor dietary habits. This long-term inflammatory environment disrupts cellular communication pathways, which leads to abnormal cell growth and survival along with tissue remodeling, thus advancing chronic diseases [6].

Oxidative stress and inflammation are not independent; rather, they exist as interconnected biological mechanisms [7]. Reactive oxygen species stimulate redox-sensitive transcription factors to express pro-inflammatory mediators through their activation [8]. Conversely, pro-inflammatory mediators stimulate additional ROS production, which generates a self-reinforcing feedback loop that worsens oxidative damage and inflammation [9]. Multiple therapeutic targets exist based on the well-established complex communication network between oxidative stress and inflammation. Current established interventions seek to balance redox states and control inflammatory pathways through various molecular mechanisms [10]. The established therapeutic approaches comprise small-molecule antioxidants that neutralize ROS and boost endogenous antioxidant function, anti-inflammatory agents that block essential inflammatory mediators, and dual acting agents such as immunometabolics and antioxidant phytochemicals, among others [10]. Despite promising results, these interventions have often met with limited widespread success in clinical practice. In other instances, their therapeutic applications have resulted in adverse health effects. Consequently, emerging therapies that can overcome these shortcomings are the subject of widespread interest for disease prevention.

This review aims to integrate the molecular basis of oxidative stress and inflammation management. Our evaluation examines established treatment strategies alongside novel experimental therapeutic methods to establish connections between scientific findings and practical healthcare needs. We seek to demonstrate how integrated therapeutic approaches can address chronic diseases through personalized medicine by targeting the multi-factorial nature of chronic diseases.

2. Molecular Interplay Between Oxidative Stress and Inflammation

The interplay between oxidative stress and inflammation represents a core, self-amplifying mechanism in the pathogenesis of numerous chronic diseases. Reactive oxygen species (ROS) serve dual roles as essential signaling molecules and as mediators of cellular damage when present in excess. Dysregulated ROS levels disrupt redox homeostasis, promote biomolecular damage, and activate pro-inflammatory signaling cascades. Conversely, inflammation enhances ROS generation through immune cell activation and redox-sensitive pathways, establishing a vicious cycle of sustained tissue injury and disease progression. The following sections detail the principal molecular mechanisms linking oxidative stress and inflammation.

2.1. Reactive Oxygen Species as Pro-Inflammatory Signaling

Reactive oxygen species, such as superoxide anion, hydrogen peroxide, and hydroxyl radicals, are mostly viewed as detrimental byproducts of metabolism, yet they also serve as essential secondary messengers in cellular signaling processes [8]. The redox-sensitive transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is activated by ROS, which plays a crucial role in controlling pro-inflammatory gene expression (Figure 1) [11]. NF-κB regulates inflammatory responses by controlling the transcription of genes that encode pro-inflammatory mediators, including cytokines (e.g., tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], interleukin-1β [IL-1β]), chemokines, and adhesion molecules, as well as enzymes such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase [12]. The activation of NF-κB by ROS occurs through the phosphorylation of its inhibitory protein IκBα, which is facilitated by IκB kinase (IKK) complex [13]. The phosphorylation of IκBα leads to its degradation, which results in the release of NF-κB dimers (p65/p50) that migrate to the nucleus to initiate inflammatory gene transcription. Thus, ROS function as destructive factors while simultaneously participating in the regulation of inflammatory responses [14].

Experimental studies suggest that ROS-driven activation of NF-κB is a critical mechanism in inflammatory diseases [15]. For instance, in LPS-stimulated RAW264.7 macrophages, pharmacological concentrations of vitamin C (supraphysiological levels achievable only through high-dose supplementation or intravenous administration) paradoxically generated ROS that suppressed NF-κB activity and reduced pro-inflammatory cytokine release [16,17]. Clinically, a meta-analysis involving patients with metabolic syndrome showed that curcuminoid supplementation (typically 500–1000 mg/day for 8 to 24 weeks) significantly reduced circulating IL-6 and TNF-α while enhancing superoxide dismutase (SOD) activity, suggesting attenuation of NF-κB-mediated inflammation through modulation of ROS levels [18,19].

2.2. Redox Regulation of Transcription Factors

Beyond NF-κB, ROS also modulate the activity of other transcription factors involved in inflammation and redox regulation (Figure 1). Among these, nuclear factor erythroid 2-related factor 2 (Nrf2) acts as an antioxidant defense master regulator [20]. Under basal conditions, Nrf2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1) [21]. Upon oxidative stress, Nrf2 dissociates from its repressor Keap1 and translocates to the nucleus, where it binds to antioxidant response elements (AREs) to induce the expression of detoxifying and antioxidant enzymes, including NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase-1 (HO-1), and various glutathione-related enzymes, such as glutathione S-transferase, which help protect cells from oxidative damage [22,23].

Preclinical data from DSS-induced colitis and LPS-stimulated macrophages has shown that FA-97 (a caffeic acid phenethyl ester derivative) activated Nrf2/HO-1 signaling, suppressed NF-κB/AP-1 activity, and decreased ROS and pro-inflammatory cytokine expression, thereby restoring gut epithelial barrier integrity [24]. In vitro, quercetin, an antioxidant compound, has been demonstrated to downregulate NOX2-derived ROS and suppress MAPK and NF-κB activity in LPS-stimulated human lung epithelial A549 cells [25]. Clinical studies corroborate these findings; for example, a randomized controlled trial of nano-formulated curcumin (80 mg/day for 24 weeks) in multiple sclerosis patients showed significant reductions in IL-6, transforming growth factor-beta (TGF-β) and oxidative markers, pointing to enhanced Nrf2 activity and suppressed inflammatory signaling [26].

In addition to Nrf2, other transcription factors are also modulated by ROS and contribute to the integration of oxidative and inflammatory pathways. Hypoxia-inducible factor 1-alpha (HIF-1α) is stabilized under oxidative conditions through inhibition of prolyl hydroxylase domain enzymes (PHDs), which require Fe²⁺ and 2-oxoglutarate for hydroxylation [27]. ROS-mediated oxidation of these cofactors reduces HIF-1α hydroxylation and proteasomal degradation, promoting the transcription of genes involved in glycolysis, angiogenesis, and inflammation [28,29]. Similarly, FOXO proteins are redox-sensitive and are regulated by a balance between AKT-mediated phosphorylation (promoting nuclear export) and direct cysteine oxidation or JNK-mediated phosphorylation (favoring nuclear retention), thereby modulating genes involved in stress response, metabolism, and immune regulation [28,29]. Activator Protein 1 (AP-1) activation is directly linked to ROS via mitogen-activated protein kinase (MAPK) signaling, with c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK) phosphorylating c-Jun and c-Fos, respectively, to enhance AP-1 DNA binding and transcription of genes regulating proliferation, survival, and inflammation [30]. STAT3 is also redox-sensitive: ROS facilitate STAT3 activation both by stimulating upstream Janus kinases (JAKs) and by oxidatively inactivating tyrosine phosphatases such as SHP-2, thereby sustaining STAT3 phosphorylation at Tyr705 and, in some contexts, Ser727 via MAPK, ultimately linking oxidative stress to chronic inflammation, oncogenesis, and fibrotic remodeling [12,31]. Together, these pathways illustrate how ROS act as both damaging and signaling molecules, integrating redox cues into gene regulatory networks.

2.3. Crosstalk Between NF-κB and Nrf2 Signaling Pathways

A pivotal mechanism in the oxidative-inflammatory network is the reciprocal regulation between NF-κB and Nrf2 pathways. These transcription factors compete for limited co-activators, such as CREB-binding protein (CBP), and exert mutually antagonistic effects [32]. NF-κB activation suppresses Nrf2-mediated transcription by sequestering CBP and increasing histone deacetylase (HDAC) recruitment to ARE, and thereby limiting the body’s antioxidant response and increasing oxidative stress. Conversely, Nrf2 activation reduces oxidative burden and inhibits NF-κB signaling through the suppression of IKK activity, thus serving as a counterbalance to chronic inflammation [33]. This reciprocal regulation is further regulated by upstream signaling pathways, including the PI3K/Akt and MAPK pathways, which integrate metabolic and stress-responsive signals. These pathways coordinate the cellular response to oxidative stress and inflammation, suggesting their potential as therapeutic targets for diseases driven by both processes [34].

Therapeutically, this antagonism has been explored using pharmacologic Nrf2 activators such as bardoxolone methyl, which has shown promising effects in reducing inflammation and improving mitochondrial function in preclinical models of polycystic kidney disease (PKD) [35]. In early-phase clinical trials involving patients with type 2 diabetes and chronic kidney disease (CKD), bardoxolone significantly improved estimated glomerular filtration rate (eGFR) within 4 weeks. However, the phase III BEACON trial was prematurely terminated due to cardiovascular safety concerns, highlighting the complexity of systemically modulating Nrf2 [36,37]. Additional clinical evidence from resveratrol supplementation in type 2 diabetes patients has shown increases in total antioxidant capacity and SOD activity, suggesting clinically relevant activation of the Nrf2 pathway [38].

Figure 1 illustrates this cross-talk: oxidative stress activates NF-κB, leading to the production of pro-inflammatory mediators (e.g., IL-6, TNF-α, COX-2), which exacerbate inflammation. Conversely, oxidative stress also triggers Nrf2 activation, promoting the transcription of antioxidant enzymes (e.g., HO-1, NQO1, GCLC) that counteract oxidative damage. NF-κB and Nrf2 exert reciprocal regulation: NF-κB can inhibit Nrf2 through CBP deprivation and Keap1 translocation, while Nrf2 suppresses NF-κB activity via IKK degradation and HO-1 activity. This bidirectional regulation highlights the dynamic interplay between pro-inflammatory and antioxidant pathways in maintaining redox homeostasis [39,40].

2.4. Mitochondrial Dysfunction and NLRP3 Inflammasome Activation

There is another important relationship between oxidative stress and inflammation, and this is mitochondrial dysfunction. Mitochondria are the main source of cellular ROS, and their malfunction can lead to the formation of high levels of ROS and the leakage of mitochondrial DNA (mtDNA) into the cytosol [41]. This mtDNA acts as a damage-associated molecular pattern (DAMP), which is recognized by the innate immune system, triggering inflammatory responses through the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome [42,43]. The activation of the NLRP3 inflammasome leads to the activation of caspase-1, which cleaves and activates pro-inflammatory cytokines IL-1β and IL-18, thereby increasing the inflammatory response [44]. Moreover, mtROS are involved in the priming and activation of the inflammasome, creating a vicious cycle of mitochondrial dysfunction and inflammation. Dysregulated mitophagy, the process by which damaged mitochondria are removed, further contributes to the persistence of mitochondrial dysfunction and heightened inflammatory signaling [45,46].

Therapeutically, strategies that directly reduce mtROS or enhance mitochondrial function are being explored to disrupt this feedback loop. Mitochondria-targeted antioxidants such as mitoquinone (MitoQ) and Mito-TEMPO, in clinical trials for neurodegenerative and cardiovascular diseases, lower mtROS and suppress NLRP3 activation in ABS-stimulated human proximal tubule epithelial cells [47,48]. Mitophagy inducers, including urolithin A, spermidine, and rapamycin derivatives, further enhance mitochondrial clearance and dampen inflammatory signaling [49,50]. Nrf2 activators, such as bardoxolone methyl, also indirectly reduce mtROS-driven NLRP3 activation in ABS-induced rat models [51], and their broader redox effects are addressed in Section 6.3.

2.5. Immune Cell Modulation by ROS

Reactive oxygen species are increasingly recognized as pivotal modulators of both innate and adaptive immunity, exerting context-dependent effects that range from host defense to the promotion of chronic inflammatory and autoimmune conditions. In macrophages, elevated ROS levels favor classical (M1) polarization, characterized by enhanced production of pro-inflammatory mediators such as IL-1β and TNF-α, alongside increased activity of iNOS and NADPH oxidase complexes [52]. This pro-inflammatory phenotype plays an essential role in pathogen clearance and the orchestration of acute immune responses; however, when sustained, it can drive tissue damage and perpetuate chronic inflammatory states. In contrast, ROS can simultaneously inhibit pathways critical for alternative (M2) macrophage polarization, including the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and signal transducer and activator of transcription 6 (STAT6) pathways, thereby impairing mechanisms involved in resolution of inflammation and tissue remodeling [24,53,54].

In the adaptive immune system, ROS are key determinants of T lymphocyte fate and function. Oxidative stress has been shown to shift the delicate balance between pro-inflammatory T helper 1 (Th1) and Th17 cells and immunoregulatory T cells (Tregs). Specifically, increased intracellular ROS promote the activation of STAT1 and STAT3 pathways, facilitating Th1 and Th17 differentiation, while concurrently suppressing the expression of forkhead box P3 (FOXP3), a master regulator of Treg development and function [55,56]. This imbalance has been implicated in the pathogenesis of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis, where excessive Th17 activity and compromised Treg function exacerbate tissue inflammation and autoimmunity in murine models [57]. Meta-analyses investigating antioxidant therapies in autoimmune disorders, including systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD), have demonstrated that redox modulation can partially restore Treg/Th17 balance and attenuate disease severity, underscoring the therapeutic potential of targeting ROS-mediated pathways [58].

Neutrophils, as the first responders of innate immunity, deploy ROS both directly and indirectly to combat pathogens [59]. One of the most striking ROS-dependent mechanisms is the formation of neutrophil extracellular traps (NETs), web-like structures composed of decondensed chromatin and antimicrobial proteins designed to immobilize and neutralize invading microorganisms [60]. While NETs are indispensable for effective host defense, aberrant or excessive NET formation (i.e., NETosis) has been implicated in sterile inflammation, vascular injury, and thrombosis [61]. Notably, elevated NETs have been documented in systemic lupus erythematosus (SLE), rheumatoid arthritis, and severe COVID-19, where their persistence correlates with disease severity, endothelial dysfunction, and heightened thrombotic risk [62,63]. These insights have spurred the development of preclinical strategies targeting NETosis, including NADPH oxidase inhibitors and peptidylarginine deiminase 4 (PAD4) inhibitors, which hold promise for clinical translation in autoimmune and thromboinflammatory disorders.

2.6. Epigenetic Control of Redox and Inflammatory Pathways

In addition to direct biochemical signaling, ROS exert profound epigenetic effects that shape the transcriptional landscape of immune and inflammatory responses [64]. Oxidative stress modulates DNA methylation patterns through the regulation of DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, often resulting in hypermethylation of anti-inflammatory gene promoters such as those encoding IL-10 and suppressor of cytokine signaling 3 (SOCS3) [65]. Such aberrant methylation patterns can lock immune cells into pro-inflammatory states, contributing to disease chronicity and, in some instances, transgenerational inheritance of inflammatory predisposition [66]. This phenomenon has been documented in conditions such as inflammatory bowel disease, systemic sclerosis, and metabolic inflammatory syndromes [67].

Histone modifications further mediate the interplay between oxidative stress and gene expression [68]. ROS can alter the activity of histone deacetylases (HDACs) and histone acetyltransferases (HATs), thereby modifying chromatin accessibility and the transcriptional activity of key inflammatory transcription factors. For example, oxidative inhibition of HDACs can enhance acetylation of the NF-κB p65 subunit, promoting sustained transcription of pro-inflammatory cytokines [69].

Non-coding RNAs, particularly microRNAs (miRNAs), represent an additional layer of epigenetic regulation sensitive to oxidative cues. Several miRNAs, including miR-155 and miR-34a, are induced by ROS and act as amplifiers of inflammation by targeting negative regulators of NF-κB and repressing AREs governed by Nrf2 [70,71], making them potential therapeutic targets in conditions characterized by chronic inflammation [72]. Recent preclinical studies have demonstrated that pharmacological modulation of these miRNAs can mitigate excessive inflammatory responses and restore redox balance [73]. Furthermore, meta-analyses support the clinical utility of circulating redox-responsive miRNAs as biomarkers for disease activity and treatment monitoring in chronic inflammatory states [74].

2.7. Metabolic Reprogramming: The Immunometabolic–Redox Interface

The dynamic interplay between oxidative stress, inflammation, and cellular metabolism, collectively termed immunometabolism, has emerged as a central theme in contemporary immunology [75]. Upon activation, macrophages and effector T cells undergo a well-characterized metabolic shift from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis, a metabolic reprogramming akin to the Warburg effect observed in rapidly proliferating tumor cells [76,77]. This metabolic shift is ROS-dependent, and accumulation of ROS strengthens the inflammatory state of cells. Importantly, this shift ensures rapid generation of ATP and biosynthetic precursors required for cytokine production, proliferation, and effector functions, but it also inherently elevates ROS production through increased activity of mitochondrial complexes and cytosolic NADPH oxidases [57,78].

Crucially, metabolic intermediates themselves serve as signaling molecules that reinforce or counterbalance redox and inflammatory pathways. For instance, succinate accumulation in activated macrophages stabilizes HIF-1α, promoting transcription of IL-1β and sustaining inflammatory signaling cascades [79,80]. In contrast, itaconate, an endogenous metabolite derived from cis-aconitate through the activity of immune-responsive gene 1 (IRG1), functions as a negative feedback regulator by inhibiting succinate dehydrogenase, dampening ROS production, and activating the Nrf2 pathway to induce expression of antioxidant and anti-inflammatory genes [81,82].

Preclinical investigations have highlighted the therapeutic promise of targeting this immunometabolic–redox axis. Derivatives of itaconate, such as 4-octyl-itaconate, have demonstrated potent anti-inflammatory and cytoprotective effects in murine models of sepsis, psoriasis, and autoimmune encephalomyelitis [83]. Early-phase clinical trials are now exploring the pharmacokinetics and therapeutic potential of synthetic itaconate analogs, signaling a promising avenue for modulating immunometabolic pathways to restore redox balance and resolve chronic inflammation. Collectively, targeting immunometabolic pathways offers a compelling strategy to modulate the redox-inflammatory axis, with mounting evidence from both animal models and early clinical trials underscoring the translational potential of metabolic reprogramming as an adjunct to conventional anti-inflammatory therapies [84].

The complex and interdependent relationship between oxidative stress and inflammation is mediated by an extensive array of molecular pathways and cellular mechanisms [85]. These include redox-sensitive transcriptional regulation, mitochondrial dysfunction, inflammasome activation, immune cell reprogramming, epigenetic modification, and metabolic shifts. A growing body of preclinical and clinical evidence underscores the therapeutic potential of targeting this oxidative-inflammatory axis. A comprehensive mechanistic understanding of these interactions is essential for the rational design of next-generation therapeutics that can simultaneously modulate redox balance and inflammatory responses in chronic disease states.

3. Pathologies Associated with Oxidative Stress and Chronic Inflammation

Oxidative stress and chronic inflammation underlie a wide range of chronic diseases. Excess ROS damage cells and activate inflammatory pathways, while persistent inflammation feeds back to amplify oxidative stress. This harmful cycle contributes to the development and progression of cardiovascular, neurodegenerative, metabolic, autoimmune, oncological, renal, pulmonary, hepatic, and other degenerative disorders outlined in detail below.

3.1. Cardiovascular Diseases

Oxidative stress and vascular inflammation are central to the pathogenesis of major cardiovascular diseases (CVDs), including atherosclerosis, coronary artery disease, myocardial infarction, and heart failure. Excess ROS, primarily generated by NADPH oxidases (NOX), dysfunctional mitochondria, and uncoupled endothelial nitric oxide synthase, drive endothelial dysfunction, a hallmark of early vascular injury [86].

Reactive oxygen species modify low-density lipoprotein (LDL) particles into oxidized LDL (oxLDL), which are internalized by macrophages through scavenger receptors such as CD36 and SR-A [87]. This process leads to foam cell formation and the development of fatty streaks, the earliest lesions of atherosclerosis. Simultaneously, ROS diminish nitric oxide bioavailability by reacting with it to form peroxynitrite, further impairing vasodilation and promoting a pro-inflammatory endothelial phenotype [86]. Chronic inflammation, mediated by interleukins (IL-1β, IL-6) and TNF-α, amplifies leukocyte adhesion and migration, contributing to plaque growth and instability. These unstable plaques are prone to rupture, triggering thrombus formation and acute coronary syndromes [88].

3.2. Neurodegenerative Diseases

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by a convergence of oxidative stress and neuroinflammation, which synergistically drive progressive neuronal loss [89].

In AD, excessive ROS generation arises from mitochondrial dysfunction and β-amyloid (Aβ) plaque deposition, which activate microglia and astrocytes [90]. Activated microglia release pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and ROS, creating a feed-forward loop of neuroinflammation and oxidative damage. Hyperphosphorylated tau protein further disrupts neuronal integrity, exacerbating oxidative injury [91]. Emerging evidence suggests that mitochondrial impairment may precede detectable amyloidosis by decades, underscoring its key role in early disease pathogenesis [92].

PD pathology hinges on mitochondrial complex I deficits [46], resulting in sustained ROS elevation within dopaminergic neurons of the substantia nigra [93]. α-Synuclein aggregates further disrupt mitochondrial function and promote oxidative stress, while neuromelanin-containing neurons are intrinsically more vulnerable due to iron accumulation and high metabolic demand [94]. Microglial activation contributes to a localized inflammatory milieu, releasing pro-inflammatory mediators and ROS that perpetuate neuronal injury [95]. Mutations in mitochondrial control genes, such as PINK1 and Parkin, impair mitophagy, aggravating ROS accumulation and dopaminergic cell death.

HD exhibits pronounced mitochondrial fragmentation, cristae alterations, and defects in oxidative phosphorylation, leading to elevated ROS and energy failure in striatal neurons [96]. Mutant huntingtin protein disrupts mitochondrial dynamics and fosters oxidative stress, which is compounded by persistent neuroinflammation involving microglial activation and elevated pro-inflammatory factors [97]. ALS pathogenesis intersects with oxidative stress through mutations in SOD1 and C9orf72, which impair ROS detoxification and mitochondrial function in motor neurons [92]. Dysfunctional mitochondria are marked by abnormal morphology, reduced ATP output, and impaired calcium buffering, which trigger inflammasome activation and glial inflammatory responses [96].

3.3. Diabetes and Metabolic Syndrome

Chronic low-grade inflammation and oxidative stress are central to the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Persistent hyperglycemia promotes ROS overproduction through multiple pathways: glucose autoxidation, the polyol pathway, and advanced glycation end-product (AGE) formation [98]. Excess ROS damage cellular components, impair insulin receptor signaling (via IRS-1 serine phosphorylation), and promote insulin resistance [99]. Inflammatory cytokines such as TNF-α, IL-6, and CRP are elevated in insulin-resistant states and exacerbate metabolic dysfunction by interfering with insulin receptor substrate phosphorylation and promoting lipolysis in adipose tissue [100]. This leads to ectopic fat deposition in liver and muscle, worsening metabolic control. Complications like diabetic nephropathy, retinopathy, and neuropathy are driven by ROS-induced endothelial injury, glomerular damage, and neuronal dysfunction [101,102].

3.4. Cancer

The relationship between oxidative stress and inflammation with cancer development is complex. ROS function as double-edged swords in tumorigenesis: while moderate levels drive cell proliferation and survival via redox signaling, excessive ROS induce genomic instability by damaging DNA, lipids, and proteins, which results in mutations in oncogenes and tumor suppressor genes [103,104]. A chronic inflammatory state creates a tumor-supportive microenvironment through cytokine-stimulated cell growth, apoptosis suppression, and immune system evasion [105]. Furthermore, tumors activate key transcription factors NF-kB, STAT3, and HIF-1α to express survival genes and genes that promote metastasis and chemoresistance [104]. The tumor microenvironment contains tumor-associated macrophages (TAMs) that produce growth factors, matrix metalloproteinases (MMPs), and ROS to support tumor progression [106].

Moreover, some cancers upregulate antioxidant systems (e.g., glutathione, Nrf2 pathway) to maintain redox balance, enhancing resistance to chemotherapy and radiotherapy [107]. The Nrf2/HO-1 axis, for instance, has a paradoxical role in inflammation and cancer progression, offering cytoprotection but also enabling chemoresistance. This paradox highlights the need for targeted redox modulation strategies that selectively disrupt tumor antioxidant defenses while sparing normal cells. Recent studies are exploring targeted redox modulation strategies, either inhibiting antioxidant defenses to sensitize tumors or exacerbating ROS to induce oxidative cell death pathways like ferroptosis [108,109].

3.5. Autoimmune and Inflammatory Disorders

Autoimmune and chronic inflammatory disorders, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE), exemplify the destructive synergy between oxidative stress and aberrant immune activation [110].

In RA, activated synovial macrophages and neutrophils generate excessive ROS, causing direct cartilage and bone damage. ROS also amplify inflammatory cascades by activating NF-κB and MAPK pathways, perpetuating cytokine production (e.g., IL-1β, TNF-α) [111]. Similarly, in IBD, oxidative stress disrupts the intestinal epithelial barrier and perpetuates mucosal inflammation through recruitment of neutrophils and activation of inflammasomes [112]. In SLE, defective clearance of apoptotic cells generates autoantigens that perpetuate autoantibody production. ROS-mediated DNA damage enhances neoepitope formation, further driving autoimmune responses. Antioxidant therapies, such as N-acetylcysteine, have shown promise in preclinical studies, but translating these approaches to routine clinical practice remains a challenge [113]. Autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease along with systemic lupus erythematosus experience tissue injury from oxidative stress while inflammation causes disease flares.

3.6. Renal Diseases

Oxidative stress and inflammation are fundamental contributors to the pathogenesis of chronic kidney disease (CKD) and its progression to end-stage renal failure. In CKD, increased ROS production arises from multiple sources, including mitochondrial dysfunction, NADPH oxidase activation, and impaired antioxidant defenses [114]. ROS generated by hyperglycemia, hypertension, and glomerular hypertension damage renal endothelial and tubular epithelial cells, disrupt glomerular filtration barriers, and activate pro-fibrotic and inflammatory signaling cascades. In particular, ROS stimulate the NF-κB pathway, leading to upregulation of inflammatory cytokines such as TNF-α, IL-1β, and monocyte chemoattractant protein-1 (MCP-1), which recruit immune cells and perpetuate renal inflammation. This interplay accelerates the decline of renal function and worsens cardiovascular outcomes in CKD patients [115].

For example, in diabetic nephropathy, the leading cause of CKD, persistent hyperglycemia induces excessive ROS that damage glomerular endothelial cells, mesangial cells, and podocytes. This disrupts the glomerular filtration barrier, causing proteinuria and progressive glomerulosclerosis [116]. In parallel, pro-inflammatory cytokines such as TNF-α, IL-1β, and MCP-1 recruit immune cells into renal tissues, amplifying fibrosis and interstitial inflammation. Evidence shows that markers of oxidative stress, such as malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), are elevated in CKD patients and correlate with declining glomerular filtration rate (GFR) and increased cardiovascular risk [117]. These findings underscore the diagnostic and therapeutic significance of targeting oxidative-inflammatory pathways in renal disease.

3.7. Pulmonary Diseases

In chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF), a destructive interplay between oxidative stress and inflammation contributes to airway remodeling and progressive loss of pulmonary function [118]. In COPD, exogenous oxidants, such as cigarette smoke and particulate matter, directly injure airway epithelial cells, while endogenous ROS produced by activated neutrophils and macrophages amplify tissue damage [119]. This oxidative burden triggers NF-κB activation, upregulating pro-inflammatory cytokines (e.g., IL-8, TNF-α) that recruit additional neutrophils and macrophages into the airways. Protease–antiprotease imbalance, driven by oxidative inactivation of antiproteases like α1-antitrypsin, further degrades alveolar walls, leading to emphysema [120].

In asthma, oxidative stress enhances airway hyperresponsiveness by inducing epithelial cell apoptosis, goblet cell metaplasia, and excessive mucus secretion. Elevated exhaled nitric oxide and hydrogen peroxide levels are clinical indicators of increased oxidative burden in asthmatic patients [121]. Similarly, in IPF, mitochondrial dysfunction and NADPH oxidase activation in alveolar epithelial cells generate ROS that induce epithelial-mesenchymal transition (EMT), fibroblast activation, and collagen deposition, leading to progressive fibrosis [122]. Thus, oxidative stress not only serves as a pathological hallmark but also a potential therapeutic target across diverse pulmonary diseases.

3.8. Liver Diseases

Oxidative stress and inflammation are central to the development of non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH) [123]. Excess lipid accumulation in hepatocytes promotes mitochondrial dysfunction and ROS generation, leading to lipid peroxidation and the formation of reactive aldehydes such as 4-hydroxynonenal (4-HNE) [123,124]. These oxidative byproducts trigger hepatocyte apoptosis and activate Kupffer cells, the liver’s resident macrophages, which secrete pro-inflammatory cytokines like TNF-α and IL-1β. This pro-inflammatory environment further activates hepatic stellate cells (HSCs), leading to extracellular matrix deposition and fibrosis [125]. Histological studies of NASH patients reveal increased levels of 8-OHdG, oxidized low-density lipoproteins (oxLDL), and infiltration of immune cells compared to simple steatosis, reflecting heightened oxidative damage and inflammation [126]. Antioxidant depletion, such as reduced glutathione (GSH) and catalase (CAT) activity, further exacerbates redox imbalance, establishing a vicious cycle that drives disease progression.

3.9. Skin and Reproductive Disorders

Oxidative stress is increasingly recognized as a major factor in chronic inflammatory skin diseases, such as psoriasis and atopic dermatitis [127]. In psoriasis, keratinocytes produce excess ROS in response to triggers like trauma or infection, which activate NF-κB and STAT3 pathways, amplifying the production of inflammatory cytokines (e.g., IL-17, IL-23) that sustain the hyperproliferative, inflamed state of psoriatic plaques. Lipid peroxidation markers and depleted antioxidant enzymes (e.g., glutathione peroxidase) are consistently observed in psoriatic lesions [128].

In reproductive health, endometriosis is a clear example in which local oxidative stress promotes chronic inflammation [129]. In endometriosis, retrograde menstruation introduces menstrual debris rich in iron and heme into the peritoneal cavity, which generates ROS via Fenton reactions. These ROS damage peritoneal cells and activate macrophages, perpetuating a pro-inflammatory peritoneal environment. Elevated peritoneal fluid levels of ROS and inflammatory cytokines (e.g., IL-6, TNF-α) are hallmarks of endometriosis [130]. Similarly, oxidative stress in polycystic ovary syndrome (PCOS) impairs follicular development, promotes low-grade inflammation, and worsens insulin resistance [131]. Clinical data show elevated circulating levels of MDA and reduced total antioxidant capacity in women with PCOS, linking redox imbalance to endocrine dysfunction and metabolic complications [132,133].

3.10. Aging

Aging is characterized by a progressive decline in cellular function driven in part by accumulated oxidative damage and persistent low-grade inflammation, a process termed “inflammaging” [134,135]. Mitochondrial ROS production increases with age due to declining respiratory chain efficiency, while antioxidant defenses such as SOD and CAT become less effective [136]. This oxidative imbalance damages DNA, proteins, and lipids, triggering cellular senescence and the senescence-associated secretory phenotype (SASP), which releases pro-inflammatory cytokines (e.g., IL-6, IL-8). This chronic, sterile inflammation contributes to tissue dysfunction and the pathogenesis of age-related diseases such as Alzheimer’s disease, cardiovascular disease, sarcopenia, and frailty [137]. Markers such as increased plasma 8-OHdG and elevated C-reactive protein levels are commonly observed in elderly populations, linking redox imbalance to systemic inflammation and age-related morbidity [138].

Table 1. Overview of major disease categories linked to oxidative stress and chronic inflammation.

Disease Category	Representative Conditions	Key Roles of Oxidative Stress	Key Roles of Chronic Inflammation	Examples of Pathogenic Mechanisms	Representative References
Cardiovascular Diseases	Atherosclerosis, coronary artery disease, myocardial infarction, heart failure	ROS modify LDL to oxLDL; reduce nitric acid bioavailability; endothelial damage	Pro-inflammatory cytokines promote leukocyte adhesion and plaque instability	Foam cell formation; plaque rupture; thrombosis	[86]
Neurodegenerative Diseases	Alzheimer’s, Parkinson’s, Huntington’s, ALS	Mitochondrial dysfunction; ROS-induced protein misfolding; neuronal oxidative damage	Activation of microglia/astrocytes; release of pro-inflammatory cytokines	β-amyloid toxicity; tau hyperphosphorylation; α-synuclein aggregation	[89]
Metabolic Disorders	Type 2 diabetes, metabolic syndrome	Hyperglycemia-driven ROS; AGE formation; impaired insulin signaling	Chronic low-grade inflammation drives insulin resistance	ROS disrupt IRS pathways; inflammatory cytokines worsen metabolic dysfunction	[98,101,102]
Cancer	Solid tumors, hematologic malignancies	DNA damage, mutagenesis; redox signaling for tumor survival	Tumor-promoting microenvironment; cytokine-mediated angiogenesis	NF-κB, STAT3, HIF-1α activation; TAM recruitment; immune evasion	[103,104]
Autoimmune & Inflammatory Disorders	RA, IBD, SLE	ROS damage cartilage and DNA; promote neoepitope formation	Sustained immune activation; cytokine-mediated tissue injury	NF-κB and MAPK activation; autoantibody generation	[110]
Renal Diseases	CKD, diabetic nephropathy	ROS from hyperglycemia and hypertension damage glomeruli and tubules	Cytokine-driven fibrosis and glomerulosclerosis	Proteinuria; interstitial inflammation; GFR reduction	[114,116]
Pulmonary Diseases	COPD, asthma, idiopathic pulmonary fibrosis	Inhaled/environmental oxidants; immune-derived ROS	Chronic airway inflammation; immune cell recruitment and remodeling	NF-κB activation; mucus hypersecretion; protease-antiprotease imbalance	[118]
Liver Diseases	NAFLD, NASH, fibrosis, cirrhosis	Lipid peroxidation; mitochondrial ROS accumulation	Kupffer cell activation; stellate cell-mediated fibrosis	4-HNE formation; inflammatory cytokine cascade	[123]
Skin Disorders	Psoriasis, atopic dermatitis	Keratinocyte ROS; lipid and DNA oxidative damage	Local immune activation; chronic skin inflammation	NF-κB/STAT3 signaling; barrier dysfunction	[127]
Reproductive Disorders	Endometriosis, PCOS	ROS from iron overload; antioxidant imbalance	Chronic ovarian/peritoneal inflammation	Macrophage activation; impaired folliculogenesis	[129,131]
Aging	Frailty, sarcopenia, functional decline	Accumulated mitochondrial ROS; oxidative DNA/protein damage	Chronic “inflammaging”; SASP cytokine secretion	Cellular senescence; tissue dysfunction	[134]

RA = Rheumatoid arthritis; IBD = Inflammatory bowel disease; NF-κB = Nuclear factor kappa-light-chain-enhancer of activated B cells; STAT3 = Signal transducer and activator of transcription 3; CKD = Chronic kidney disease; MAPK = Mitogen-activated protein kinase; HIF-1β = Hypoxia-inducible factor-1 beta; TAM = Tumor-associated macrophages; GFR = Glomerular Filtration Rate; 4-HNE = 4-Hydroxynonenal; COPD = Chronic obstructive pulmonary disease; NAFLD = Non-alcoholic fatty liver disease; NASH = Non-alcoholic steatohepatitis; PCOS = Polycystic ovary syndrome; SLE = Systemic lupus erythematosus; LDL = Low-density lipoprotein; oxLDL = Oxidized low-density lipoprotein; ALS = Amyotrophic lateral sclerosis.

summarizes the key pathologies caused by the combined effects of oxidative stress and chronic inflammation. Collectively, oxidative stress and chronic inflammation form a self-perpetuating cycle that contributes to the onset and progression of numerous chronic diseases. This imbalance drives persistent tissue injury and organ dysfunction, underscoring the importance of targeting these pathways for improved diagnostics and therapies.

4. Established Therapeutic Strategies Targeting Oxidative Stress and Inflammation

Chronic oxidative stress and persistent inflammation form a self-perpetuating cycle that underlies many diseases such as cardiovascular disorders, neurodegeneration, metabolic syndrome, autoimmune diseases, and cancer. Excess reactive oxygen species (ROS) activate inflammatory signaling, while pro-inflammatory cytokines amplify ROS generation. Disrupting this destructive loop relies on four established therapeutic categories: direct antioxidants, conventional anti-inflammatory drugs, targeted biologics and inhibitors, immunometabolic strategies, and nutraceuticals with dual antioxidant–anti-inflammatory actions.

4.1. Direct Antioxidant Agents

Direct antioxidants primarily function by directly scavenging ROS or by replenishing endogenous antioxidant systems such as glutathione [139]. Historically, the clinical use of direct antioxidants has focused on naturally occurring molecules such as vitamins E and C, N-acetylcysteine (NAC), and coenzyme Q10 (CoQ10). Vitamins C and E have dominated this category.

4.1.1. Vitamin C (Ascorbic Acid)

This is a water-soluble antioxidant that neutralizes superoxide, hydroxyl radicals, and peroxynitrite, while regenerating other antioxidants, such as vitamin E (α-tocopherol) [140]. Beyond its classical radical-scavenging function, vitamin C modulates several redox-sensitive signaling pathways that influence both antioxidant and inflammatory responses. It activates Nrf2, which induces the transcription of cytoprotective enzymes such as HO-1, SOD, and glutathione peroxidase (GPx). Concurrently, it suppresses NF-κB activation by stabilizing IκBα and attenuating IKK activity, thereby downregulating pro-inflammatory gene transcription [141]. As a cofactor for prolyl hydroxylases, vitamin C also regulates HIF-1α stability, linking redox homeostasis to cellular hypoxic responses [142]. In preclinical models, high-dose vitamin C reduces oxidative DNA damage and endothelial dysfunction in atherosclerosis LPS+IFNγ-stimulated rat macrovascular endothelial cells [142]. Interestingly, large clinical trials like the Heart Protection Study and Physicians’ Health Study showed that vitamin C supplementation alone did not significantly reduce cardiovascular events [143,144,145]. A meta-analysis by Bjelakovic and coworkers similarly found no consistent benefit for mortality or cancer prevention, despite strong biochemical rationale [146], a conclusion similarly noted by Lee and coworkers [147].

4.1.2. Vitamin E (Tocopherols and Tocotrienols)

This lipid-soluble antioxidant protects cellular and mitochondrial membranes from lipid peroxidation while modulating intracellular signaling cascades [148]. By regulating protein kinase C activity, vitamin E indirectly suppresses NF-κB signaling, leading to reduced inflammatory mediator production [149]. Tocotrienols, structurally distinct isoforms, further potentiate cytoprotective responses by activating Nrf2 and inducing phase II antioxidant enzymes, including HO-1 and NQO1 [150]. These effects highlight vitamin E as both a lipid-phase antioxidant and a regulator of redox-sensitive signaling pathways. Preclinical studies demonstrate its role in preventing LDL oxidation and atherogenesis [151,152]. However, clinical trials such as the HOPE study and subsequent meta-analyses revealed that vitamin E supplementation did not consistently lower cardiovascular or cancer risk and may even slightly increase all-cause mortality at high doses [143,153,154,155]. These findings have fueled skepticism regarding the utility of generic antioxidant supplementation for disease prevention.

Table 2. Tocopherol and tocotrienol isomers: structural features and key properties.

Isomer	Structure	Biological Properties
α-Tocopherol		Highest affinity for α-tocopherol transfer protein (α-TTP) → dominant plasma/tissue form and highest “biological activity”; non-α isoforms are retained far less (β ≈ 38%, γ ≈ 9%, δ ≈ 2% of α affinity) [156,157].
β-Tocopherol		Lower α-TTP affinity than α → reduced hepatic export/retention; antioxidant activity but less studied clinically vs. α-T [156,157].
γ-Tocopherol		Efficient RNS (e.g., peroxynitrite) scavenger; anti-inflammatory and anticancer activities; low α-TTP affinity limits circulating levels [157,158].
δ-Tocopherol		Preclinical anticancer signals (apoptosis, growth inhibition) reported; very low α-TTP affinity → minimal retention [157].
α-Tocotrienol		Potent neuroprotection independent of classical antioxidant action (e.g., 12-LOX/c-Src–linked pathways); protective in cellular and animal ischemia models; generally lower α-TTP transport but higher cellular uptake than tocopherols reported [159,160,161].
β-Tocotrienol		Less characterized; shares enhanced membrane dynamics of T3s; limited direct clinical data; lower α-TTP handling vs. α-T [157].
γ-Tocotrienol		Stimulates Insig-dependent ubiquitination and degradation of HMG-CoA reductase (distinct from statin competitive inhibition) → mechanistic basis for lipid-lowering; additional radioprotective/anti-inflammatory and anticancer activities reported [162,163].
δ-Tocotrienol		Strongest HMG-CoA reductase degradation among vitamin E forms in vitro; clinical lipid outcomes are mixed (some studies show no LDL-C reduction overall; HDL-C increases are reported in subgroups). Also investigated for anticancer activity [162,164,165,166].

Abbreviations: α-TTP, α-tocopherol transfer protein; RNS, reactive nitrogen species; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; T, tocopherol; T3, tocotrienol.

summarizes the key tocopherol and tocotrienol isomers, capturing the structural variations and their relevant properties.

4.1.3. N-Acetylcysteine (NAC)

NAC remains an exception among direct antioxidants, with clear, guideline-supported clinical applications. As a precursor of glutathione (GSH), NAC restores intracellular GSH stores depleted during oxidative injury [167]. Its influence on signaling is mediated through inhibition of NF-κB activation, which reduces the transcription of pro-inflammatory cytokines and adhesion molecules [168]. In parallel, NAC enhances Nrf2-dependent transcription of ARE-driven genes, augmenting cellular defense against oxidative stress [169]. Its well-established use in acute acetaminophen (paracetamol) toxicity illustrates this mechanism: NAC replenishes hepatic GSH, enabling detoxification of the hepatotoxic metabolite NAPQI [168]. Beyond toxicology, long-term oral NAC (600–1200 mg/day) has demonstrated benefit in chronic obstructive pulmonary disease (COPD) by reducing exacerbations and improving mucociliary clearance [170,171]. Recent randomized controlled and meta-analyses in COPD patients have shown that both oral NAC and inhaled NAC reduce exacerbation rates and improve recovery parameters, though effects on lung function decline remain modest (e.g., hazard ratio ~0.65 for exacerbations, shortened hospital stay, improved PaO₂) [172,173]. However, a large multicenter trial in mild-to-moderate COPD reported no significant reduction in exacerbation rates or improvement in FEV₁ with high-dose NAC over two years [174], highlighting discordant outcomes depending on patient population and study design.

4.1.4. Coenzyme Q10 (CoQ10)

CoQ10 is an endogenous component of the mitochondrial electron transport chain which exerts antioxidant effects by regenerating other antioxidants and mitigating lipid and protein peroxidation [175]. It suppresses NF-κB–mediated pro-inflammatory signaling and enhances Nrf2-driven antioxidant enzyme transcription, including HO-1 and SOD, which collectively support cellular protection against oxidative stress and inflammation [176,177]. In animal models, CoQ10 mitigates myocardial ischemia-reperfusion injury and improves mitochondrial function in neurodegenerative disease models [178]. Small clinical trials suggest modest improvements in endothelial function, statin-induced myopathy, and heart failure symptoms [179,180]. However, robust evidence for hard clinical endpoints base on meta-analyses is lacking, and CoQ10 is not universally incorporated into standard practice [181,182].

Together, these direct antioxidants illustrate how promising mechanistic and preclinical findings do not always translate into robust clinical endpoints, highlighting the complex nature of redox balance in human disease. Despite limitations, NAC remains an exception with clear clinical benefit for glutathione repletion where depletion is profound.

4.2. Conventional Anti-Inflammatory Agents

Conventional anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, form the mainstay for managing acute and chronic inflammatory conditions and exert important indirect effects on oxidative stress by attenuating upstream inflammatory signals that drive ROS production [183].

4.2.1. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs include drugs such as ibuprofen, naproxen, and celecoxib, and are among the most widely prescribed anti-inflammatory medications [184]. They exert their anti-inflammatory and analgesic effects primarily by inhibiting cyclooxygenase (COX-1 and COX-2) enzymes, which catalyze the conversion of arachidonic acid to pro-inflammatory prostaglandins [185]. By suppressing prostaglandin synthesis, NSAIDs indirectly reduce ROS generation linked to neutrophil activation and vascular inflammation [183]. Clinically, NSAIDs provide symptomatic relief in osteoarthritis, rheumatoid arthritis, and other musculoskeletal conditions, yet their well-known risks, including gastrointestinal ulceration, renal impairment, and increased cardiovascular events, limit long-term use [186,187]. Interestingly, selective COX-2 inhibitors (coxibs) were developed to minimize gastrointestinal toxicity but introduced new concerns about thrombotic cardiovascular risk [188,189].

4.2.2. Corticosteroids

Corticosteroids, such as prednisone and dexamethasone, remain cornerstone therapies for acute inflammatory flares and chronic autoimmune conditions. They modulate multiple pathways by binding glucocorticoid receptors, suppressing pro-inflammatory gene expression such as NF-κB, AP-1, while inducing anti-inflammatory mediators [190,191]. This broad immunosuppressive effect indirectly lowers oxidative stress by dampening the production of ROS by activated immune cells. Preclinically, glucocorticoids reduced LPS-induced oxidative injury in murine models of lung and liver inflammation [192]. Clinically, their potent anti-inflammatory effects are well documented in asthma, inflammatory bowel disease, alcoholic hepatitis, and systemic autoimmune diseases [193,194,195]. Despite profound efficacy, prolonged corticosteroid use is constrained by well-documented adverse effects, including immunosuppression, osteoporosis, hyperglycemia, and adrenal suppression [196,197].

4.3. Targeted Biologics and Small-Molecule Inhibitors

The past two decades have witnessed a paradigm shift from broad-spectrum anti-inflammatory drugs to targeted biologics and small-molecule inhibitors that block specific cytokines or intracellular signaling pathways involved in inflammation. Among these, biologic disease-modifying antirheumatic drugs (DMARDs), including anti-TNF-α agents (infliximab, adalimumab), IL-1β monoclonal blockers (canakinumab), and IL-6 receptor antagonists (tocilizumab), have transformed the management of rheumatoid arthritis, Crohn’s disease, and other autoimmune disorders [198,199]. By neutralizing key pro-inflammatory cytokines, these agents indirectly reduce downstream ROS production in inflamed tissues [198]. For example, the landmark CANTOS trial demonstrated that targeting IL-1β with canakinumab significantly reduced recurrent cardiovascular events in patients with elevated C-reactive protein [200], confirming the clinical relevance of cytokine-driven oxidative and inflammatory pathways in atherosclerosis [198,201].

Likewise, Janus kinase (JAK) inhibitors, which block intracellular cytokine signaling, have emerged as effective oral alternatives [202]. First-generation JAK inhibitors (tofacitinib, baricitinib) and second-generation agents (upadacitinib, abrocitinib) demonstrate efficacy in rheumatoid arthritis, ulcerative colitis, and alopecia areata by dampening multiple pro-inflammatory cytokine signals [203,204]. Second-generation JAK inhibitors, characterized by enhanced selectivity, show improved safety profiles with fewer off-target effects in recent long-term trials [205,206]. Although these biologics and small molecules do not directly neutralize ROS, they effectively break the inflammatory–oxidative cycle by suppressing upstream cytokine and signaling pathways. However, their clinical use requires careful monitoring due to associated risks such as immunosuppression, thrombosis, malignancy, and they do not directly scavenge ROS [207,208].

4.4. Immunometabolic Agents

Emerging immunometabolic strategies leverage conventional metabolic regulators that afford dual benefits: metabolic control and redox modulation. These agents exemplify how targeted pharmacology can simultaneously reshape energy metabolism and mitigate oxidative stress in chronic diseases.

Metformin, the cornerstone of type 2 diabetes treatment, exerts potent antioxidant effects beyond glycemic control. It partially inhibits mitochondrial complex I, decreasing reverse electron transfer-mediated ROS generation and enhancing AMPK activity, which promotes autophagy, mitochondrial quality control, NAD⁺ salvage, and Nrf2-driven antioxidant responses [209]. In human immune cells, metformin activates AMPK and FOXO3, inducing SOD2 and cytochrome c expression, thereby reducing ROS levels [210]. In endothelial and vascular models, metformin suppresses NADPH oxidase (NOX4) expression and lipid peroxidation (e.g., reduced MDA levels), reinforcing its direct redox-modulating capacity [211]. Beyond diabetes, metformin has demonstrated efficacy in animal models of aging and lung fibrosis through mitochondrial protective mechanisms, enhancing mitochondrial biogenesis (via PGC-1α/SIRT1), preserving ATP, reducing ROS, and alleviating senescent phenotypes [209].

Statins, widely used lipid-lowering agents, also possess direct redox-modulating effects independent of LDL reduction [212]. In kidney tubular cells exposed to lipid overload, statins downregulate NOX2 and NOX4 expression, reduce ROS production, and improve mitochondrial morphology and function. These findings suggest broader protective potential in metabolic and CKD contexts [213].

Immunometabolic modulators, such as GLP-1 receptor agonists (e.g., liraglutide, semaglutide) and SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin), further enrich this dual-action therapeutic class. Though not yet formally categorized under “immunometabolic agents,” accumulating evidence demonstrates their capacity to improve mitochondrial integrity, reduce mtROS levels, enhance mitophagy, and lower pro-inflammatory cytokines in metabolic disease model [214]. Despite their proven benefit, statin intolerance and metformin’s renal clearance constraints limit broader applicability [215,216].

4.5. Natural Polyphenols and Nutraceuticals

Research shows that the Mediterranean diet, which contains antioxidants, polyunsaturated fatty acids, and polyphenols, effectively reduces inflammation and oxidative stress markers that lead to better health and longer life expectancy [217,218]. This suggests their usefulness as adjunct (not approved prescription drugs) in managing chronic diseases associated with oxidative stress and systemic inflammation. Naturally derived polyphenols and nutraceuticals are increasingly recognized as adjuncts for their multitargeted antioxidant and anti-inflammatory effects.

4.5.1. Natural Polyphenols (Curcumin, Resveratrol, and Others)

Curcumin, the bioactive compound in turmeric (Curcuma longa), has garnered significant attention. It modulates NF-κB, Nrf2, and MAPK signaling and scavenges ROS [219]. In preclinical models, curcumin demonstrated cardioprotective effects by reducing infarct size, oxidative markers, and inflammatory cytokines [220]. Curcumin supplementation was reported to improve the quality of life in cancer patients undergoing chemotherapy [221,222]. Meta-analyses confirm their potential benefits in IBD [223], arthritis [224,225], and metabolic inflammation [226]. A 2023 meta-analysis of randomized controlled trials (13 RCTs, ~785 subjects) in metabolic syndrome patients found curcumin supplementation reduced markers such as TNF-α, CRP, and malondialdehyde (MDA), and improved HDL-cholesterol levels [227]. Broader umbrella reviews by Dehzad et al., 2023 and Qui et al., 2025 synthesizing multiple meta-analyses reported consistent reductions in CRP, TNF-α, IL-6, and MDA, and enhanced total antioxidant capacity and SOD activity across diverse populations [228,229].

Likewise, resveratrol, abundant in grapes and red wine, activates SIRT1 and Nrf2 pathways, downregulating inflammatory cytokines and oxidative stress markers [230]. In patients with type 2 diabetes, a meta-analysis of six RCTs (533 participants) demonstrated that resveratrol supplementation significantly reduced CRP, lipid peroxide levels, and 8-isoprostanes, while increasing GPx and CAT levels, though effects on IL-6 and TNF-α were less consistent [231]. Other nutraceuticals, including dietary polyphenols like anthocyanins from berries, phenolic acids, and gingerols, have shown anti-inflammatory effects and reduction in oxidative markers in joint and metabolic health disorders. However, controlled trial data remain limited. Despite promising results in metabolic and cardiovascular studies, translating natural polyphenols/nutraceuticals into clinical practice remains hindered by poor bioavailability, variability in supplement formulations, and the absence of regulatory drug-level approval [226].

4.5.2. Omega-3 Fatty Acids and Vitamin D

Omega-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid, have well-documented anti-inflammatory and antioxidant effects [232]. They decrease arachidonic acid-derived eicosanoids and modify phospholipid membrane composition, providing anti-inflammatory and modest antioxidant effects [233]. A 2024 systematic review and meta-analysis in T2DM found that omega-3 supplementation significantly reduced TNF-α and increased total antioxidant capacity, albeit without significant effects on MDA, CRP, SOD, or IL-6 in all settings [234]. Additional meta-analyses confirm benefits for rheumatoid arthritis symptom reduction and cardiovascular event risk lowering in patients [235,236].

Vitamin D exerts immunomodulatory effects, and its deficiency is linked to human inflammatory disorders [237]. The active form, 1,25-dihydrovitamin D, not only exerts potent anti-inflammatory effect by modulating both innate and adaptive immune responses but also modulates redox homeostasis. Immunologically, it controls the performance of immune cells by downregulating Th1 and Th17 cell function, leading to reduced production of pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ) while simultaneously upregulating Th2 and Treg cell function, leading to increased secretion of anti-inflammatory cytokines IL-4 and IL-10 [238]. Multiple epidemiological studies report the beneficial effects of vitamin D supplementation for managing the autoimmune diseases rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease, as well as type 1 diabetes mellitus [239]. Beyond these actions, vitamin D has been shown to influence oxidative stress pathways by upregulating antioxidant defenses, such as Nrf2 signaling and glutathione synthesis. For example, supplementation has been associated with increased GPx activity and decreased IL-6 levels in patients with post-COVID-19 condition, suggesting a dual role in mitigating both inflammation and oxidative stress [240].

Table 3. Approved and adjunct therapies for management of oxidative stress and chronic inflammation.

Therapy Class	Approved Indications	Key Agent(s)	Preclinical Evidence	Clinical Evidence	Key Limitations & Inconsistencies
Classical Small-Molecule Antioxidants	Vitamin E (deficiency); Vitamin C (scurvy); NAC (acetaminophen overdose)	Vitamin E, Vitamin C, NAC, CoQ10 (Antioxidant only)	Vitamin E and C scavenge ROS [142], [151,152]; NAC replenishes glutathione stores [167]	Meta-analyses show inconsistent benefit in CVD, cancer, neurodegeneration [143,144,145]; NAC effective for acetaminophen toxicity [170,171]	Vitamin E: increased stroke risk; vitamin C: poor bioavailability; CoQ10: variable benefit in heart failure; NAC: no robust evidence for other chronic conditions [174]
Conventional Anti-inflammatories (NSAIDS & Corticosteroids)	RA, IBD, autoimmune flares, pain, asthma	NSAIDs (aspirin, ibuprofen, naproxen); Corticosteroids (prednisone, dexamethasone) (Dual: indirect antioxidant)	NSAIDs inhibit COX → reduce prostaglandins → limit ROS from neutrophils ([184]; Corticosteroids suppress NF-κB and pro-oxidant gene expression [192]	Well-established RCTs for inflammation, pain, autoimmune flares [186,187]; corticosteroids are standard of care for asthma, IBD, severe flares [193,194,195]	NSAIDs: GI bleeding, CV events, renal effects; corticosteroids: immunosuppression, osteoporosis, metabolic syndrome; neither directly scavenges ROS
Anti-inflammatory Biologics	RA, IBD, psoriasis, residual CV inflammation	Infliximab, adalimumab, canakinumab, tocilizumab (Dual: anti-inflammatory)	TNF-α & IL-1β blockade reduces ROS-generating inflammation [198,199]	CANTOS trial (canakinumab) reduced CV events [200]; broad RCT support for RA/IBD [198,201]	High cost, injection-site reactions, risk of infections, no direct ROS scavenging
Small-Molecule Immune Pathway Inhibitors	RA, psoriatic arthritis, ulcerative colitis	Tofacitinib, baricitinib (Dual: anti-inflammatory)	JAK/STAT inhibition downregulates cytokine-driven ROS [202]	Meta-analysis supports efficacy in RA/UC [205,206]	Infection risk, malignancy signal, no direct ROS clearance
Immunometabolic Modulators	T2DM (metformin); dyslipidemia & CV prevention (statins)	Metformin, atorvastatin (Dual: indirect antioxidant & anti-inflammatory)	Metformin activates AMPK → less mitochondrial ROS [210,211]; statins lower NADPH oxidase activity [213]	Large meta-analyses support CV risk reduction; metformin lowers CRP/IL-6 [241]	Statin intolerance; metformin limited in CKD
Adjunct Nutraceuticals/Polyphenols	Not formally approved as drugs. Widely used as adjunct	Curcumin, resveratrol, EGCG, quercetin (Dual: direct antioxidant + anti-inflammatory)	Modulate NF-κB, Nrf2, MAPK [217,218]; scavenge ROS directly [219]	Meta-analyses: curcumin for IBD levels [224,225], [227]; resveratrol lowers CRP, TNF-α [231]	Poor oral bioavailability; dose inconsistency; variable supplement quality; lack of large-scale drug-level approval

Abbreviations: RA = Rheumatoid arthritis; IBD = Inflammatory bowel disease; NAC = N-acetyl cysteine; CoQ10 = Coenzyme Q (Ubiquinone); CVD = Cardiovascular disease; NSAIDs = Non-steroidal ant-inflammatory drugs; COX = Cyclooxygenases; CV = Cardiovascular; GI = Gastrointestinal; RCT = Randomized control trial; NF-κB = Nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α = Tumor Necrosis Factor alpha; IL-1β = Interleukin-1 beta; JAK/STAT = Janus kinase/signal transducers and activators of transcription; AMP = Adenosine monophosphate; T2DM = Type 2 diabetes mellitus; CKD = Chronic kidney disease; Nrf2 = Nuclear factor erythroid 2-related factor 2; MAPK = Mitogen-activated protein kinase; NADPH = Nicotinamide adenine dinucleotide phosphate; EGCG = Epigallocatechin gallate.

summarizes the key established therapies in clinical use for managing pathologies caused by the combined effects of oxidative stress and chronic inflammation. While established antioxidant and anti-inflammatory therapies have delivered measurable benefits for acute and chronic inflammatory diseases, limitations remain, chiefly poor specificity for intracellular ROS sources, inconsistent clinical efficacy in complex diseases, and adverse effects among others that constrain long-term use. These challenges underscore the need for novel agents and combination approaches, which will be discussed in forthcoming sections.

5. Limitations and Challenges of Established Therapeutic Strategies

Despite decades of intensive research and widespread clinical use, conventional antioxidant and anti-inflammatory therapies have not consistently translated robust experimental promise into uniformly successful patient outcomes. Their implementation in clinical practice remains constrained by key scientific, clinical, and systemic barriers. The following sections highlight principal limitations that continue to hinder the optimal impact of these therapies on diseases underpinned by oxidative stress and chronic inflammation.

5.1. Poor Bioavailability and Inefficient Delivery

A major limitation for many established antioxidants, particularly natural polyphenols such as curcumin, quercetin, and resveratrol, is inherently poor bioavailability. These molecules show low water solubility, poor intestinal absorption, and rapid hepatic metabolism, resulting in subtherapeutic plasma and tissue concentrations when taken orally [242]. For example, although curcumin shows potent antioxidant and anti-inflammatory effects in vitro and in animal models, clinical trials have often demonstrated modest or inconsistent benefits for inflammatory bowel disease and osteoarthritis due to these pharmacokinetic constraints [243]. Delivery technologies such as liposomal encapsulation, polymeric nanoparticles, and solid lipid nanoparticles have shown promise in overcoming bioavailability barriers, but their safety, scalability, and cost-effectiveness require further validation before widespread adoption [244].

5.2. Lack of Target Specificity and Biomarker Reliability

Many conventional antioxidants act through broad, non-targeted scavenging of ROS, without adequately distinguishing between harmful oxidative stress and physiological redox signaling essential for cellular adaptation and host defense [245]. Reactive oxygen species function as both harmful and beneficial agents within the body because they perform essential immune functions while aiding cell signaling and enabling mitochondrial adaptation. As such, excessive or non-targeted antioxidant supplementation may blunt adaptive stress responses, such as mitochondrial biogenesis and hormesis, potentially impairing beneficial physiological resilience. Meta-analyses of vitamin E and beta-carotene supplementation, for example, have not shown consistent cardiovascular benefit and, in some studies, have increased mortality risk when used indiscriminately [146,153,246]. Furthermore, current biomarkers, including CRP, TNF-α, and IL-6, provide only broad information about systemic inflammation; they do not detect localized redox conditions or tissue-specific damages [3]. The lack of reliable and validated biomarkers hampers proper patient stratification and real-time therapeutic outcome assessment.

5.3. Disease and Patient Heterogeneity

Redox-related and inflammatory conditions present clinical heterogeneity that makes therapeutic efficacy challenging to achieve. The baseline redox status together with therapeutic response is influenced by multiple factors, including genetic polymorphisms in antioxidant enzymes (GSTM1, SOD2, NQO1), age-related immune dysfunction, microbiome diversity, and environmental exposures [247,248]. For instance, individuals with GSTM1 null polymorphisms demonstrate altered detoxification capabilities that influence the effectiveness of specific antioxidants. In addition, patient responses to therapeutic interventions in chronic diseases like diabetes, neurodegeneration, and cardiovascular disorders frequently show substantial variation because these conditions inherently involve multiple factors. As a result, standard monotherapy trials often yield inconsistent or marginal effect sizes that fail to reach clinical significance for heterogeneous conditions like cardiovascular disease or neurodegeneration [249,250].

5.4. Limitations of Monotherapy Approaches

Oxidative stress and chronic inflammation involve highly redundant and interconnected pathways. Conventional monotherapies that target a single pathway frequently fail to produce sustained benefit because compensatory mechanisms bypass the therapeutic block [251,252]. For example, statins demonstrate well-documented pleiotropic antioxidant and anti-inflammatory effects alongside lipid lowering [253], but residual cardiovascular risk persists, necessitating adjunct therapies. Similarly, NSAIDs effectively reduce prostaglandin-mediated inflammation but do not address upstream cytokine networks or oxidative damage at the mitochondrial level [254]. Combination therapies that integrate antioxidants, immunomodulators, and metabolic agents are increasingly explored to address this mechanistic complexity but require robust systems biology approaches and refined trial designs to balance safety and synergy [255].

5.5. Safety Risks and Long-Term Uncertainty

While short-term use of NSAIDs and corticosteroids is clinically effective, long-term therapy is constrained by well-known adverse effects including gastrointestinal bleeding, cardiovascular risk, immunosuppression, and metabolic disturbances [186,256]. Similarly, high-dose antioxidant supplements may paradoxically increase oxidative injury by interfering with adaptive redox signaling [146,257]. For instance, vitamin E supplementation at supraphysiological doses (> or =400 IU/d) has been linked to increased all-cause mortality in large meta-analyses [146,153]. Additionally, polypharmacy situations that affect older adults become more relevant because of elevated drug–drug and drug–nutrient interactions. These risks highlight the need for long-term safety monitoring, validated biomarkers for early detection of adverse events, and robust real-world data to complement findings from controlled trials.

5.6. Regulatory and Quality Control Challenges

The majority of natural antioxidant and anti-inflammatory agents are sold as dietary supplements or functional foods which are subject to less stringent regulatory oversight compared to pharmaceutical drugs [258]. The ambiguous regulatory status enables commercial products to contain inconsistent levels of active ingredients while affecting purity and bioavailability levels [259]. This lack of standardization complicates reproducibility in clinical trials and limits clinician and patient confidence in consistent therapeutic benefit. Harmonized global standards for quality control, labeling, and clinical validation are essential to translate promising compounds into reliable clinical interventions.

5.7. Practical Barriers: Adherence and Accessibility

Finally, the real-world impact of these therapies depends on sustained patient adherence, which remains challenging for both pharmacological and lifestyle-based interventions. Dietary modification, physical activity, and stress reduction have clear benefits for oxidative and inflammatory balance but are notoriously difficult to implement and maintain without continuous support and engagement [260,261,262]. The accessibility and effectiveness of treatments also depend heavily on socioeconomic and cultural factors. Healthcare disparities together with education inequalities and digital competence variations exacerbate health disparities while restricting the implementation of new therapeutic approaches. These barriers necessitate the need for integration of digital health tools and personalized coaching together with community engagement in healthcare models to enhance patient adherence and long-term outcome maintenance [263,264].

Collectively, these multifaceted challenges underscore why established antioxidant and anti-inflammatory therapies have yet to fully deliver on their biological promise in complex chronic diseases. Addressing these limitations will require novel agents, innovative delivery systems, validated precision biomarkers, robust combination regimens, and new models for patient-centered implementation.

6. Emerging Strategies and Perspectives Targeting Chronic Oxidation-Inflammation Related Diseases

Despite significant advances, the limited efficacy of conventional antioxidant and anti-inflammatory interventions, coupled with suboptimal targeting of intracellular sources of ROS and unintended off-target consequences, has necessitated the development of next-generation therapeutic strategies. These mechanism-driven and system-integrated approaches, including catalytic enzyme mimetics, mitochondrial-targeted antioxidants, and Nrf2 activators, among others, aim to neutralize oxidative stress at its root, modulate upstream signaling cascades, and align more closely with endogenous defense and repair mechanisms (Figure 2).

6.1. Catalytic Enzyme Mimetics

Catalytic enzyme mimetics represent a fundamental mechanistic innovation in overcoming the stoichiometric limitations of conventional antioxidants (Figure 2) [265]. Unlike direct scavengers that neutralize ROS on a stoichiometric (i.e., 1:1) basis, these compounds emulate the activity of endogenous antioxidant enzymes such as SOD, CAT, and GPx, catalytically and repeatedly converting superoxide anions, hydrogen peroxide, and other ROS into less reactive species. Notable examples include Manganes-porphyrins (e.g., MnTE-2-PyP, MnTBAP, MnBuOE, AEOL-10150), Manganese-salens such as EUK-8, EUK-134, and EUK-207, and newer nanozyme constructs, including Manganese-based single-atom catalysts soluble in biological systems [266].

6.1.1. Manganese Porphyrins

Manganese porphyrins, particularly MnBuOE (BMX-001) and MnTE-2-PyP (BMX-010), have demonstrated potent SOD-like activity alongside CAT-like functions in preclinical disease models. In rodent lung irradiation models, MnTE-2-PyP (BMX-010) significantly reduced fibrosis, inflammatory macrophage infiltration, and TGF-β levels, preserving long-term respiratory function [267,268]. Notably, BMX-001 is currently undergoing phase 1/2 clinical trials as a radioprotective agent in glioma patients, highlighting its translational promise [268].

Furthermore, preclinical studies demonstrate that MnTBAP reduces mitochondrial superoxide in NADPH-stimulated rat aortic smooth muscle cell model of hypertension and limits ex vivo endothelial dysfunction in apolipoprotein(E)-deficient mice model of atherosclerosis [269,270]. Similarly, in vivo studies using PC3 and LNCaP cells demonstrated that Mn-porphyrins enhanced the tumoricidal effect of radiation and reduced oxidative damage to normal prostate tissue adjacent to the prostate tumor in the presence of radiation [271].

Similarly, manganese porphyrins such as AEOL-10150 offer potent catalytic antioxidant activity by mimicking SOD and CAT. Recent studies have revealed its effectiveness in mitigating oxidative injury across multiple tissues and toxic challenges. AEOL-10150 has been reformulated to allow higher tolerated doses, extended half-life, and improved brain and lung pharmacokinetics. In rodent models of nerve-agent intoxication (e.g., DFP), a single daily subcutaneous dose (40 mg/kg) significantly protected against oxidative stress, neuronal death, microglial activation, memory impairment, and mortality [272,273]. AEOL-10150 has also demonstrated robust protection in pulmonary oxidative injury models. In CEES (mustard-gas analog) and chlorine gas inhalation assays, AEOL-10150 reduced inflammatory cell infiltration, lipid peroxidation, DNA oxidative markers (e.g., 8-OHdG, 4-HNE), and lung function decline, even when administered post-exposure [274,275]. Notably, AEOL-10150 treatment in a mouse myocardial ischemia–reperfusion model prevented succinate-driven mitochondrial ROS accumulation right after reperfusion, preserved mitochondrial membrane potential, reduced cardiomyocyte apoptosis, and limited adverse cardiac remodeling over eight weeks [273]. It has also shown efficacy in mitigating radiation-induced lung injury in non-human primates, further underscoring its broad organ protection capability [276,277]. Importantly, while AEOL-10150 has reached Phase I human safety trials and demonstrated good tolerability, supporting its translational potential, clinical translation remains limited by pharmacokinetic challenges and potential off-target pro-oxidant effects [278].

6.1.2. Manganese Salens

Manganese salens mimetics, including EUK-134 and EUK-207, mimic both SOD and CAT activities and have demonstrated neuroprotective and anti-fibrotic effects in diverse preclinical models [279]. For instance, EUK-134 prevented diaphragm muscle weakness in monocrotaline-induced pulmonary hypertension in rats by reducing oxidative actin modifications and preserving contractile function [280]. Furthermore, EUK-134 has been shown to delay neurodegeneration in ALS mouse models [281]. Additional preclinical studies using Manganese salen mimetics have shown protective effects in epilepsy, ischemia–reperfusion injury, amyloid peptide toxicity, and skeletal muscle atrophy [267,282].

6.1.3. Nanozyme and Single-Atom Mimetics (SAzymes)

SAzymes represent a newer generation of enzyme mimetics. Recent manganese-based single-atom catalysts (Mn-N₄ SACs) have demonstrated multi-enzyme mimicking activity for SOD, CAT, and GPx, operating at low energy barriers (≈0.08 eV) for superoxide dismutation [283], opening avenues for precise intracellular redox modulation in neuroinflammatory and metabolic disease models [284,285]. A notable agent, calmangafodipir (PledOx), a manganese–calcium complex that mimics both SOD and CAT, has demonstrated hepatoprotective effects in patients undergoing oxaliplatin-based chemotherapy [286,287], although its clinical use has been tempered by concerns about short plasma half-lives and the risk of off-target pro-oxidant effects [288,289]. Similarly, reviews confirm single-atom nanozymes’ promise in biomedical ROS control [290].

Despite promising findings, the field must address challenges related to limited suboptimal pharmacokinetics, dose-dependent pro-oxidant/redox-cycling risks, and uncertainties about long-term tissue accumulation/toxicity [288]. Current research focuses on enhancing organelle-specific targeting through conjugation with mitochondria-penetrating peptides and the development of biocompatible nanocarrier systems to improve half-life and minimize systemic exposure.

6.2. Mitochondria-Targeted Antioxidants

Given that mitochondria are the principal source of intracellular ROS via electron transport chain leakage, mitochondria-targeted antioxidants have emerged as an important therapeutic strategy (Figure 2) [291]. Conventional antioxidants often fail to accumulate in mitochondria at therapeutically relevant concentrations. To address this, emerging therapeutic strategies exploit lipophilic cationic moieties or mitochondria-penetrating peptides to achieve selective mitochondrial uptake. Key examples include MitoQ, a ubiquinone analog linked to triphenyl phosphonium (TPP), and SkQ1, a plastoquinone derivative with potent ROS-scavenging capacity within mitochondrial membranes [292].

SkQ1 and related plastoquinone derivatives, conjugated to TPP, have demonstrated potent antioxidant activity. In aged mice, chronic SkQ1 administration significantly accelerated wound healing, reduced neutrophil infiltration, enhanced macrophage-mediated inflammation resolution, and improved tissue repair in dermal injury models [293]. In a model of cancer-induced cachexia in mice, SkQ1 attenuated muscle wasting and improved contractile function, exhibiting sex-specific responses [294]. Additional preclinical studies confirm that SkQ1 improves mitochondrial morphology and reduces oxidative markers in models of aging and neurodegeneration [291], while SkQ1 has shown additional protective effects against retinal degeneration [295,296].

MitoQ similarly accumulates in mitochondria to scavenge ROS. Recent reviews highlight its protective effects in models of neurodegeneration and metabolic disease [297], noting improved mitochondrial respiration, reduced lipid peroxidation, and enhanced cell survival. Preclinical models have demonstrated that MitoQ attenuates cardiac fibrosis and vascular stiffening [298]. Similarly, studies in myocardial ischemia reperfusion injury diabetic models have shown that MitoQ not only scavenges mitochondrial ROS but also activates the PINK1/Parkin pathway, thereby facilitating mitophagy and preventing cardiomyocyte apoptosis under hyperglycemic stress [299].

Elamipretide (SS-31), a mitochondria-penetrating tetrapeptide, binds cardiolipin to preserve mitochondrial integrity and indirectly mitigate ROS production [300]. In the PROGRESS-HF Phase 2 trial, intravenous elamipretide was well tolerated and associated with reductions in left ventricular end-diastolic and end-systolic volumes in patients with heart failure with reduced ejection fraction, though the primary endpoint was not met [301]; however, large-scale randomized efficacy trials remain limited. Notably, concerns persist regarding membrane depolarization at high doses and incomplete understanding of long-term safety impacts on mitochondrial biogenesis and dynamics [300]. Emerging strategies include exosome-mediated delivery and redox-responsive nanocarriers to enhance mitochondrial targeting and controlled release. Current challenges involve preserving membrane integrity at high doses, achieving sustained retention, and understanding long-term effects on mitochondrial dynamics and biogenesis.

6.3. Nrf2 Pathway Activation

An additional frontier in redox-targeted therapy focuses on pharmacologically activating the Nrf2–Keap1–ARE axis, which orchestrates the transcription of a wide array of cytoprotective genes, including those encoding HO-1, NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-synthesizing enzymes (Figure 2) [302]. Although phytochemicals such as sulforaphane, curcumin, and resveratrol exhibit mild Nrf2 activation, pharmacological activation of Nrf2 offers a promising therapeutic strategy to achieve more potent and sustained induction by enhancing endogenous cytoprotective capacity. Notable Nrf2 activators in clinical use are bardoxolone methyl (CDDO-Me) and dimethyl fumarate (DMF) [303]. Here, bardoxolone methyl (CDDO-Me), a potent synthetic Nrf2 activator, exemplifies this strategy. Following early promise of renal improvement in diabetic kidney disease (DKD) patients, the phase III BEACON trial was stopped due to increased heart failure risk [35,304,305,306], underscoring the critical need for careful benefit–risk assessment. More recent phase II data from the TSUBAKI and AYAME trials (2023) demonstrate sustained improvement in estimated glomerular filtration rate (eGFR) without worsening cardiac function when administered to lower-risk cohorts, reaffirming its clinical potential under refined protocols [307].

Dimethyl fumarate (DMF), approved for multiple sclerosis and psoriasis, stabilizes Nrf2 by modifying Keap1 cysteines and promoting its nuclear translocation [308]. Recent in vitro and clinical studies show DMF reduces neuroinflammation, enhances antioxidant gene expression, and correlates with better clinical responses in MS patients, especially those showing a greater shift in immune cell profiles and Nrf2 signaling across different doses [309,310]. Research into more selective, tissue-specific Nrf2 activators and redox-switchable prodrugs is ongoing, with the goal of minimizing off-target electrophilic stress and optimizing therapeutic windows. Here, CDDO-Me derivatives and synthetic triterpenoids have shown promise by enhancing specificity and potency but require precision dosing to avoid excessive electrophilic stress [311]. However, clinical translation constrained by risks of excessive pathway activation (context-dependent oncogenic signaling), prior off-target toxicities (e.g., fluid retention with bardoxolone), and the need for biomarker-guided dosing/selection. A key translational priority is the development of reliable biomarkers, such as NQO1 luciferase reporters or circulating HO-1 fragments, for precise patient stratification and therapeutic monitoring to identify the patients most likely to benefit from pathway modulation.

6.4. Immunometabolic Modulators

The intersection of immunometabolism and redox biology offers a promising therapeutic axis for modulating inflammation and oxidative stress (Figure 2). Key examples include itaconate and its derivatives, which activate Nrf2 and inhibit pro-inflammatory pathways [82]; metformin and other AMPK activators, which suppress NF-κB signaling and support redox balance; and sirtuin activators, which enhance mitochondrial function and anti-inflammatory responses via SIRT1 and SIRT3. These agents highlight the therapeutic potential of targeting metabolic checkpoints in immune regulation.

6.4.1. Itaconate and Its Derivatives

Derived from the IRG1-encoded enzyme in activated macrophages, endogenous itaconate inhibits succinate dehydrogenase, dampening mitochondrial ROS while activating Nrf2 signaling [82,312]. Synthetic analogs such as dimethyl itaconate and 4-octyl itaconate replicate these effects with enhanced cellular uptake. In murine and cell models of chronic lymphocyte leukemia and chronic pain, dimethyl itaconate reduced chronic neuroinflammatory pain, suppressed IL-1β and TNF-α, and increased Nrf2 expression in dorsal root ganglia and spinal cord; effects were abolished when Nrf2 was inhibited [313,314]. In bleomycin-induced mouse fibrotic lung models, dimethyl itaconate alleviated fibroblast-to-myofibroblast differentiation by decreasing TXNIP expression and suppressing ROS via Nrf2 activation [315]. Moreover, additional preclinical studies demonstrated that dimethyl itaconate and 4-octyl-itaconate offered enhanced cell permeability and potency while demonstrating robust anti-inflammatory and antioxidant effects in models of sepsis, autoimmune encephalomyelitis, and ischemia–reperfusion injury models [83]. A 2023 study further showed that dimethyl itaconate confers long-term “trained immunity,” with epigenomic and metabolic reprogramming leading to resistance against Staphylococcus aureus infection and altered cytokine responsiveness [316]. Despite these promising reports, translation to routine clinical translation is challenged by pharmacokinetic limits (e.g., short half-life for itaconate derivatives), inter-individual metabolic variability, and safety uncertainties with chronic modulation.

6.4.2. Metformin and AMPK Activators

Beyond its antihyperglycemic effect, metabolic agents such as metformin and AICAR indirectly modulate ROS production by activating AMP-activated protein kinase (AMPK) and downregulating the NLRP3 inflammasome [317], thus reducing mitochondrial ROS production and inflammatory cytokine release. Emerging data links metformin’s anticancer benefits partly to modulation of redox-sensitive pathways and ferroptotic cell death involving Nrf2/HO-1 suppression [318,319]. Additionally, metformin induces metabolic rewiring including alterations in TCA-cycle intermediates that overlap with oxidative and immune signaling responses [320].

6.4.3. Sirtuin Activators (SRT2104 and Related STACs)

Sirtuin activators, including resveratrol and newer synthetic compounds such as SRT2104, are potent SIRT1 activators which bolster antioxidant defenses, modulate NF-κB signaling, and promote mitophagy [321,322]. Long-term treatment in diabetic rodent models with SRT2104 improved endothelial function, reduced oxidative and vascular injury, and increased muscle mass preservation [323]. In ischemia–reperfusion studies, SRT2104 shifted microglial polarization toward anti-inflammatory M2 phenotypes and inhibited NF-κB activation, offering neuroprotection in cerebral injury models [324]. Future approaches may integrate immunometabolic reprogramming with checkpoint blockade or pro-resolving mediator therapies to target the redox–inflammation nexus more comprehensively. Such combinations may enhance efficacy in chronic inflammatory and metabolic disorders by synchronizing metabolic adaptation, antioxidant response, and immune resolution.

6.5. Nanotechnology-Enabled Targeting

Nanotechnology-based delivery systems have emerged as powerful tools to overcome key limitations of antioxidant therapies, such as poor solubility, rapid degradation, and lack of tissue specificity (Figure 2) [325,326]. Modern nanoformulations enhance stability, bioavailability, and targeted accumulation of antioxidant payloads, making them promising candidates for redox-based interventions. Examples include nano-formulated polyphenols (nano-curcumin, nano-quercetin), cerium oxide nanoparticles (CeO₂ NPs) and manganese oxide nanozymes with SOD- and CAT-like catalytic activity, and ROS-responsive polymer nanoparticles that release antioxidants in high-ROS microenvironments [327].

6.5.1. Cerium Oxide Nanoparticles (CeO₂ NPs)

CeO₂ NPs, or “nanoceria”, exhibit enzyme-mimetic behavior, facilitating catalytic scavenging of ROS via Ce³⁺/Ce⁴⁺ redox cycling. In human neuroblastoma (SH-SY5Y) cells, CeO₂ NPs synthesized via green methods significantly improved viability after H₂O₂-induced oxidative insult, reduced lipid and protein oxidation, and enhanced endogenous antioxidant enzyme activities, demonstrating strong neuroprotective effects [328,329]. In a murine model of ischemic stroke, ceria NPs coated with dl-3-n-butylphthalide (NBP) preserved mitochondrial integrity, reduced infarct volume, and improved cognitive and motor outcomes by protecting the blood–brain barrier and suppressing neuronal apoptosis [330]. Preclinical investigations have demonstrated that CeO₂ NPs mitigate ischemic brain injury and neurodegeneration in Alzheimer’s disease models by modulating local redox states [331,332]. Recent biocompatibility assessments in human neuronal/glial cell lines confirm minimal cytotoxicity even at μg/mL doses, supporting cautious advancement toward clinical application [329].

6.5.2. Manganese-Based Nanozymes (MnO₂/Mn₃O₄)

Manganese oxide nanoparticles, including MnO₂-BSA composites and Mn₃O₄ formulations, exhibit multienzymatic antioxidant activity mimicking CAT, SOD, and GPx. In epithelial lung cell lines, MnO₂-BSA NPs significantly reduced hydrogen peroxide-induced apoptosis and oxidative markers without disrupting endogenous antioxidant systems [333,334]. Mn₃O₄ nanozymes similarly prevented DNA, lipid, and protein damage while preserving cellular redox balance in oxidative-stressed HEK293 cells [334,335].

6.5.3. Polymeric Micelles and Nanogels

These carriers are typically composed of amphiphilic block copolymers with ROS-cleavable chemical bonds, such as thioethers, disulfides, or boronic esters, that are stable in physiological conditions but degrade upon encountering elevated ROS levels [336]. These ROS-responsive polymer micelles and smart nanogels release therapeutic payloads selectively within high ROS microenvironments, representing another innovation with potential applications in conditions such as colitis, ischemia–reperfusion injury, and cancer [337]. For example, Yu et al. (2024) demonstrated micelles based on carboxymethyl chitosan–methionine conjugates, where thioether groups oxidize to sulfone in ROS-rich intestinal epithelial cells lines, triggering the selective release of encapsulated astaxanthin and reducing H₂O₂-induced oxidative intestinal damage in vitro [338]. In models of psoriatic skin inflammation, Yao et al. (2024) developed supramolecular polymer micelles responsive to ROS that release an encapsulated TYK2 inhibitor, achieving targeted reduction in mitochondrial oxidative stress and inflammation with minimal systemic exposure in imiquimod-induced psoriasis mouse model and TNF-α/IL-17A-stimulated human keratinocytes (HaCaT cells) [339].

6.5.4. Hybrid Nanocarriers with Polyphenols and Anti-Inflammatory Agents

Hybrid nanocarriers co-encapsulating antioxidants with anti-inflammatory agents provide dual-action control of oxidative damage and immune dysregulation [340]. For instance, Diez-Echave et al. (2021) prepared silk-fibroin nanoparticles loaded with quercetin that prevented colonic inflammation in DSS-induced mouse models of ulcerative colitis, restoring tight junction protein expression and reducing leukocyte infiltration [341]. In cardiovascular applications, Ahmed et al. (2021) reported that a nano-formulation of quercetin significantly improved endothelial function and oxidative status in a rat model of metabolic syndrome [342]. Curcumin-loaded lipid–polymer hybrid nanoparticles have also been shown to overcome bioavailability limitations. In DSS-induced colitis and tumor-bearing Alzheimer’s disease mouse models, these carriers improved oral absorption and brain delivery of curcumin compared to traditional formulations [343,344]. However, widespread translation is hindered by potential long-term nanozyme accumulation, systemic/immune toxicity, and regulatory challenges. A crucial research priority is ensuring the biocompatibility, long-term safety, and regulatory standardization of these nano-formulations to facilitate clinical translation.

6.6. Combination and Synergistic Therapies

Given the multifactorial nature of chronic diseases, monotherapy with antioxidants often proves insufficient (Figure 2). As such, there is growing interest in synergistic therapeutic strategies that simultaneously target ROS production, mitochondrial dysfunction, and inflammation. Recent studies have demonstrated that combining mitochondria-targeted antioxidants with catalytic enzyme mimetics or other redox modulators can achieve enhanced therapeutic efficacy. For example, co-formulations of mitochondria-targeted antioxidants, such as MitoQ with SOD mimetics, have demonstrated enhanced cardioprotection in preclinical myocardial ischemia-reperfusion injury aged mouse models [345]. Other promising approach involves co-administration of MitoQ, a mitochondria-targeted form of ubiquinone, with alpha-lipoic acid (ALA). In aged rat models of myocardial ischemia-reperfusion injury (IRI), this combination therapy significantly outperformed either agent alone, reducing infarct size, decreasing lipid peroxidation and LDH release, and restoring mitochondrial function. Notably, it also normalized mitochondrial dynamics by upregulating fusion markers (Mfn1/Mfn2) and downregulating fission proteins, while enhancing expression of mitophagy and biogenesis-related genes such as PINK1 and Foxo1 [345]. These findings suggest that MitoQ and ALA work synergistically to preserve mitochondrial integrity and promote cardioprotection in the aged myocardium.

Furthermore, triple-combination regimens in preclinical trials, such as MitoQ combined with melatonin and mitochondrial transplantation, have demonstrated superior outcomes in aged hearts, markedly improving cardiac function, reducing oxidative damage, and enhancing mitochondrial biogenesis through the SIRT1/PGC-1α/NRF2 signaling axis [346,347]. These advanced combination therapies represent a promising strategy to address the complexity of redox imbalance in age-related cardiovascular disease.

Beyond mitochondrial therapeutics, combinatorial approaches involving dietary lipids have also shown benefit. The addition of omega-3 fatty acids, particularly EPA and DHA, to statin therapy has been associated with additive cardiovascular protection. Recent reviews suggest that omega-3 fatty acids may enhance the biosynthesis of specialized pro-resolving mediators (SPMs), amplifying anti-inflammatory and antioxidant effects when co-administered with statins [348]. A meta-analysis involving over 40,000 patients reported that this combination significantly reduced the incidence of myocardial infarction, major adverse cardiovascular events (MACE), unstable angina, and inflammatory markers such as high-sensitivity C-reactive protein (hsCRP) compared to statin monotherapy [349]. In heart failure patients, omega-3 supplementation alone has been found to reduce circulating levels of pro-inflammatory cytokines, such as TNF-α and IL-6, while enhancing total antioxidant capacity (TAC), suggesting a potent immunomodulatory and redox-regulatory effect that could synergize with other interventions [350]. These data support the rationale for combining lipid-based therapies with pharmacological agents to achieve broader therapeutic outcomes. Despite promising preclinical results, clinical evidence is limited, with heterogeneous trial designs, dosing/sequence optimization challenges, drug–drug interaction risks, and heterogeneous patient responses presenting translational hurdles.

Emerging clinical frameworks now integrate systems biology and artificial intelligence (AI) to guide the design of multi-agent antioxidant regimens. Adaptive clinical trial platforms are exploring combinations of mitochondrial-targeted antioxidants, Nrf2 activators, enzyme mimetics, and immunometabolic modulators. These precision medicine strategies aim to personalize therapy based on molecular phenotypes and predicted drug interactions, ultimately improving efficacy and reducing adverse outcomes in redox-related diseases.

6.7. Stem Cell-Derived Therapies and Exosomes

Recent advancements in regenerative medicine have highlighted mesenchymal stem cell (MSC)-derived exosomes as promising therapeutic agents capable of modulating immune responses and mitigating oxidative stress in a range of disease contexts (Figure 2) [351]. These extracellular vesicles, secreted through paracrine mechanisms, are enriched with bioactive molecules, including antioxidant enzymes such as SOD and CAT, as well as regulatory microRNAs like miR-21 and miR-146a, that exert systemic anti-inflammatory and redox-stabilizing effects [352,353].

Several recent studies have demonstrated the therapeutic potential of MSC-derived exosomes in both preclinical and translational settings. In models of neurodegeneration, myocardial infarction, and inflammatory bowel disease, exosomes have shown the ability to suppress ROS, improve mitochondrial function, and promote cellular survival. For instance, exosomes derived from adipose-derived MSCs enhanced PI3K/Akt-Nrf2 signaling in a H₂O₂-stimulated dental follicle cell (DFCs) model of oxidative dental root injury, significantly reducing ROS production, inhibiting apoptosis, and promoting osteogenic differentiation [354]. Similarly, in models of photoaged or chemically damaged skin, MSC-derived exosomes have been shown to reverse oxidative damage by activating the Nrf2 pathway, underscoring their potential in dermatological and cosmetic applications [355].

Beyond localized tissue effects, systemic administration of MSC exosomes has been associated with neuroprotective and anti-senescence effects. Preclinical models highlight the potential of MSC-derived exosomes to protect neurons in Parkinson’s disease, preserve cardiomyocyte viability after infarction, and restore blood–brain barrier integrity in neuroinflammatory conditions using LPS- or H₂O₂-induced BV-2 microglia cells [356]. In SAMP8 aged mice, intravenous delivery of MSC-derived exosomes improved cognitive function and reduced oxidative neuronal injury via SIRT1 activation, suggesting potential utility in addressing age-related neurodegenerative processes [355]. In inflammatory conditions such as Crohn’s disease, cell-based therapies using MSCs, though not yet exclusively exosome-based, have already reached clinical trial stages, with the ADMIRE-CD trial reporting clinical remission linked to reductions in local inflammatory and oxidative mediators [357].

Despite their promise, key challenges moving forward include standardizing exosome isolation and characterization protocols, ensuring scalability under good manufacturing practice (GMP) conditions, and establishing robust regulatory frameworks for cell-derived therapeutics. Moreover, pharmacokinetics, biodistribution, and long-term safety data are still being elucidated. Regulatory frameworks remain in flux, with exosomes straddling the interface between biologics and advanced therapeutic medicinal products. Nevertheless, as evidence grows, MSC-derived exosomes represent a compelling and biologically sophisticated tool in the fight against oxidative stress- and inflammation-related diseases, offering a cell-free alternative with reduced immunogenic risk and enhanced bioactive specificity.

6.8. Integrated Lifestyle and Digital Therapeutics

Lifestyle modification remains a cornerstone of redox balance management (Figure 2). Robust evidence from meta-analyses indicates that adherence to Mediterranean-style and DASH dietary patterns, characterized by high intakes of polyphenols and omega-3 fatty acids, can reduce biomarkers of oxidative stress and chronic inflammation [358,359]. Structured exercise regimens are known to upregulate endogenous antioxidant enzymes such as SOD2 and GPx and reduce lipid peroxidation [360], while mindfulness practices and sleep optimization can modulate neuroinflammatory pathways and circadian redox regulation [361]. Increasingly, digital health technologies, including wearable biosensors, AI-driven coaching applications, and gamified behavioral tools, offer scalable solutions to personalize and reinforce these interventions. Future research should focus on integrating real-time ROS biosensing and personalized feedback loops to sustain long-term lifestyle adherence and synergize with pharmacological treatments.

6.9. Regulatory and Ethical Considerations

As these innovative strategies, from nanoparticles to cell-based interventions, advance, their successful implementation depends on the parallel evolution of regulatory and ethical frameworks to ensure safe and equitable access [362]. Nanomedicine, AI-driven diagnostics, gene editing, and complex biologics challenge traditional approval pathways and require harmonized international standards for safety, efficacy, and reproducibility. Robust data privacy protections, equitable access models, and meaningful stakeholder engagement are essential to maintain public trust and ensure that the benefits of these emerging therapies reach diverse populations without exacerbating existing health disparities [363].

Table 4. Summary of promising emerging therapies for management of oxidative stress and chronic inflammation.

Therapy Class	Development Stage	Key Agent(s)	Advantages over Existing Therapies	Preclinical Evidence	Clinical Evidence	Key Limitations/Challenges
Catalytic Enzyme Mimetics	Calmangafodipir: Phase II–III (limited EU use) for chemo liver injury; Others: Preclinical–Early Phase I	Tempol, EUK-134 (Dual: direct ROS dismutation)	Offer sustained antioxidant activity without rapid consumption, unlike classical antioxidants; mimic endogenous defense systems	SOD/CAT mimetics reducing oxidative damage in stroke, neurodegeneration models [265,266]	Limited Phase I trials; no Phase III data; calmangafodipir Phase II–III results show hepatoprotection in chemo patients [286,287]	Specialized use; Short plasma half-life; delivery and dosing challenges; toxicity profile not fully characterized
Mitochondria-Targeted Antioxidants	Early Phase I–II	MitoQ, SkQ1 (Dual: mitochondrial ROS scavenging + anti-inflammatory)	Target the primary site of ROS generation, offering superior mitochondrial protection and bioenergetic restoration compared to systemic antioxidants	Decreases mitochondrial superoxide, protects endothelial function in CVD/aging animal models [298,299]	Early Phase I/II in CVD, Parkinson’s, macular degeneration [291,301]	Limited large RCT data; variability in mitochondrial targeting; potential off-target effects
Nrf2 Activators	Phase II–III (halted/terminated)	Bardoxolone methyl (Dual: activates endogenous antioxidant defenses + anti-inflammatory)	Activate a broad endogenous cytoprotective program, unlike single-target antioxidants; modulate redox and inflammatory gene networks	Potent Nrf2 inducer reducing oxidative stress/inflammation in CKD/diabetes models [302,308]	Phase II/III halted due to increased heart failure and fluid retention [35,304,305,306,309,310]	Cardiovascular safety concerns; off-target effects limit clinical translation
Metabolic Intermediates/Derivatives	Preclinical	Itaconate, 4-octyl-itaconate (Dual: immunometabolic reprogramming + Nrf2 antioxidant/anti-inflammatory activation)	Reprogram immune cell redox tone for precision immunomodulation, addressing inflammation at its root rather than symptomatically	Regulates macrophage metabolism; induces Nrf2 pathway; attenuates inflammation in sepsis/autoimmunity models [313,314,323]	Preclinical only, no human trials to date	Unknown pharmacokinetics, safety, and dosing in humans
Nanoparticle & Advanced Delivery Systems	Early Phase I–II	Curcumin nanoparticles, cerium oxide nanoparticles (Dual: enhanced ROS scavenging + inflammation modulation)	Improve solubility, targeting, and intracellular delivery of redox agents, surpassing limitations of poorly absorbed or rapidly cleared molecules	Improved bioavailability and ROS neutralization in cancer, wound healing models [328,329]	Early Phase I–II trials in oncology, wound care [364,365]	Long-term bioaccumulation concerns; scalability and regulatory hurdles
Stem Cell-Derived Therapies and Exosomes	Early Phase I–II (safety/feasibility); Select agents approved: Alofisel (EU) for complex perianal fistulas in Crohn’s; TEMCELL (Japan) for steroid-refractory GVHD	Mesenchymal stromal cells (BM-/AD-/UC-MSCs); MSC-derived extracellular vesicles/exosomes (e.g., MSC-Exos; cardiosphere-derived exosomes)	Broad antioxidant and anti-inflammatory effects, lower immunogenicity, off-the-shelf potential	Reduce ROS and inflammation, enhance repair in MI, stroke, ARDS, IBD, liver injury models, [355,356,366]	Early Phase I/II trials show safety/feasibility (ARDS, IBD, OA) [357]; no large Phase III trials for redox indications	Product heterogeneity, manufacturing/scale-up, dosing, and regulatory challenges
Combination/Synergistic Therapies	Small-scale adjunct clinical trials; no large factorial RCTs	Examples: mito-targeted antioxidants + NOX inhibitors; antioxidants (e.g., NAC/curcumin) + anti-cytokine biologics (anti-TNF); metabolic reprogrammers (itaconate derivatives) + anti-fibrotics; omega-3/SPM analogs + standard anti-inflammatories	Concurrent multi-node targeting across ROS generation, redox signaling, and immune effector pathways; potential dose-sparing and improved durability versus monotherapy	Synergistic suppression of ROS, NF-κB, fibrosis, and organ injury in CVD, NASH, CKD, and arthritis models [345,346,347,348]	Small adjunct trials show additive benefits (e.g., NAC add-on in COPD, curcumin + NSAID in RA, omega-3 + statin lowering CRP); limited large factorial RCTs to confirm synergy [349,350]	Drug–drug interactions and cumulative AEs; dosing/sequence optimization; heterogeneity in trial designs; regulatory/reimbursement complexity for combinations

Abbreviations: SOD = Superoxide dismutase; CVD = Cardiovascular disease; Nrf2 = Nuclear factor erythroid 2-related factor 2; BM = bone marrow; AD = adipose-derived; UC = umbilical cord; EVs = extracellular vesicles; NOX = NADPH oxidase; MI = myocardial infarction; ARDS = acute respiratory distress syndrome; IBD = inflammatory bowel disease; OA = osteoarthritis; RCT = randomized controlled trial; AEs = adverse events.

summarizes the emerging therapies in preclinical testing for managing pathologies caused by the combined effects of oxidative stress and chronic inflammation, along with key translational challenges and limitations. Collectively, these emerging strategies signify a shift from generic antioxidant supplementation towards precision-engineered, mechanism-based, and system-integrated approaches for redox-inflammatory modulation. Although they show robust preclinical efficacy, their clinical translation is hindered by unresolved issues in bioavailability, targeted delivery, safety, and regulatory approval. Bridging the persistent gap between experimental promise and clinical success will require rigorously designed trials with standardized endpoints and long-term evaluation. Continued innovation, rigorous validation, and equitable implementation will be pivotal to unlocking the full therapeutic potential of targeting oxidative stress and inflammation in complex chronic diseases.

7. Conclusions and Future Perspectives

Oxidative stress and chronic inflammation remain major contributors to the development and progression of numerous diseases. While traditional antioxidant and anti-inflammatory therapies have shown limited clinical success due to challenges such as poor bioavailability, non-specific targeting, and safety concerns, emerging strategies now offer more precise and multi-faceted solutions. Catalytic enzyme mimetics, mitochondria-targeted antioxidants, Nrf2 activators, immunometabolic regulators, advanced nanocarriers, and stem cell-based therapies represent promising directions to overcome the limitations of established approaches. Combining these with personalized lifestyle interventions and digital health tools may enhance treatment effectiveness and long-term patient adherence. Looking ahead, rigorous clinical trials, robust biomarker development, and global collaboration will be essential to translate these innovations into safe, effective, and equitable therapies. By integrating mechanistic insight with technological advances, the next generation of redox- and inflammation-targeted interventions holds strong promise for improving chronic disease management.