Redox Balance, Mitohormesis, and Organ Stress in Type 2 Diabetes Mellitus: Mechanistic Insights and the Therapeutic Role of SGLT2 Inhibitors

Abstract

Oxidative stress and chronic low-grade inflammation are recognized key drivers of diabetic complications. Lysosomal dysfunction, cellular senescence, and inter-organ stress signaling further aggravate the Redox–Inflammation–Organ Stress Axis in type 2 diabetes mellitus (T2DM). Recent studies suggest that reactive oxygen species (ROS) are not always harmful. Through mitohormesis, mild and transient increases in ROS levels can trigger antioxidant defenses, strengthen mitochondrial function, and limit chronic inflammation. Evidence from caloric restriction, exercise, and ketone body studies supports this adaptive redox balance, underscoring the importance of maintaining a “hormetic window” rather than indiscriminate antioxidant supplementation. In our prospective study, sodium-glucose cotransporter 2 inhibitor treatment significantly reduced albuminuria and serum levels of inflammatory markers, e.g., tumor necrosis factor receptors 1 and 2, while paradoxically increasing urinary 8-hydroxy-2′-deoxyguanosine levels and biological antioxidant potential (BAP), suggestive of adaptive ROS responses consistent with mitohormesis. Concomitant glucagon-like peptide-1 receptor agonist use emerged as an independent explanatory factor for increased urinary levels of oxidative stress markers, suggesting that multiple metabolic therapies converge on shared hormetic pathways. Emerging evidence that stressed adipocytes can communicate mild ROS signals via extracellular vesicles expands this paradigm to inter-organ mitohormesis. Collectively, these insights caution against indiscriminate antioxidant use and underscore the therapeutic potential of controlled redox modulation to disrupt the vicious cycle of senescence, inflammation, and organ stress. Incorporating redox biomarkers like urinary 8-hydroxy-2′-deoxyguanosine, reactive oxygen metabolite derivatives, and BAP into clinical monitoring, alongside pharmacological and lifestyle interventions, may facilitate the realization of precision metabolic medicine for multi-organ protection in T2DM.

1. Introduction

Type 2 diabetes mellitus (T2DM) is now recognized as being driven not only by persistent hyperglycemia but also by chronic oxidative stress and low-grade inflammation [1]. These interrelated processes accelerate cardiovascular, renal, and hepatic complications, underscoring the necessity for therapeutic approaches that modulate redox balance and inflammatory pathways [2,3,4].

Excess reactive oxygen species (ROS) activate redox-sensitive transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), leading to the upregulation of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 [5]. These cytokines subsequently impair mitochondrial function and promote sustained ROS production, creating a self-perpetuating vicious cycle that contributes to endothelial dysfunction, insulin resistance, and tissue fibrosis. Recent evidence also highlights that lysosomal dysfunction amplifies oxidative stress and inflammation, further promoting cardiovascular and metabolic complications [6]. At low levels, however, ROS can act as signaling molecules that activate protective antioxidant pathways—a concept termed mitochondrial hormesis or mitohormesis [7,8]. These mechanisms involve nuclear factor erythroid 2-related factor 2 (Nrf2) and related transcription factors, helping to maintain tissue homeostasis and potentially extending lifespan [9]. As a physiological example, regular moderate physical activity generates low-level oxidative stress, which induces an anti-inflammatory environment by upregulating antioxidant and anti-inflammatory defense systems [10]. Nutritional states such as caloric restriction and nutritional ketosis also engage mitohormetic pathways [11].

Oxidative stress-induced molecular and organelle damage—including endoplasmic reticulum and mitochondrial dysfunction as well as cellular senescence—can cause chronic inflammation in patients with diabetes. This can further exacerbate metabolic and vascular injury [12]. This vicious cycle has been implicated in the pathogenesis of cardiovascular disease, sarcopenia, osteoarthritis, and cancer.

Direct antioxidant supplementation has not consistently shown benefits and sometimes even increases disease risk [13,14]. However, therapeutic strategies that modulate rather than abolish ROS signaling have garnered attention. This principle aligns with the hormesis framework, which has long been discussed in biogerontology and drug development [15,16].

Sodium–glucose cotransporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering agents, have demonstrated remarkable cardiorenal protective effects in large outcome trials. Recent experimental and clinical findings suggest that these benefits may involve the modulation of oxidative stress, inflammation, and engagement of mitohormetic pathways. In this review, we summarize emerging data on how SGLT2 inhibitors may attenuate organ stress through adaptive redox responses and compare these insights with those from other hormetic models such as caloric restriction, exercise, aging, and inter-organ ROS signaling.

2. Mechanisms of Mitohormesis

Mitohormesis refers to the adaptive biological response triggered by a transient and moderate increase in mitochondrial ROS levels. Unlike pathological oxidative stress, which causes irreversible molecular damage, mild elevations of ROS levels serve as signaling cues that activate protective stress response pathways.

Key molecular sensors of mitohormesis include the following:

• Nrf2 activates the transcription of antioxidant enzymes, such as manganese superoxide dismutase (MnSOD), catalase, and glutathione peroxidase [17].
• AMP-activated protein kinase (AMPK) senses energy depletion, promotes autophagy, and enhances metabolic flexibility [18].
• Sirtuin (SIRT)1 and SIRT3: nicotinamide adenine dinucleotide-dependent deacetylases that regulate mitochondrial protein acetylation and energy metabolism. SIRT3 is localized in mitochondria and has been implicated in promoting mitochondrial function and oxidative stress resistance, whereas SIRT1 interacts with peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) to enhance mitochondrial biogenesis and antioxidant responses [19].
• NF-κB: its suppression mitigates chronic inflammation by downregulating pro-inflammatory cytokines, such as TNF-α and IL-6 [5].

As illustrated in Figure 1, these pathways collectively improve mitochondrial quality control, enhance antioxidant capacity, reduce chronic inflammation, and promote cellular resilience. Physiological stimuli, such as caloric restriction [20], exercise [21], and nutritional ketosis [22], and pharmacological interventions, such as SGLT2 inhibition, are all thought to engage these hormetic processes. The net effect is the preservation of tissue homeostasis and the potential delay of age-related complications, provided ROS levels remain within a “hormetic window.”

Preclinical data also support the involvement of SGLT2 inhibitors in mitohormetic pathways. For instance, Tomita et al. demonstrated in murine models of diabetic kidney disease that SGLT2 inhibition promoted ketone body-induced suppression of mechanistic target of rapamycin complex 1 (mTORC1), leading to enhanced autophagic flux, improved mitochondrial quality control, and adaptive redox balance [23]. These findings suggest that SGLT2 inhibitors may indirectly engage mitohormetic signaling by modulating mitochondrial function and stress adaptation, thereby providing a mechanistic bridge between experimental findings and clinical observations.

3. Caloric Restriction and Mitohormesis

Caloric restriction is widely recognized as a potent nongenetic intervention that extends lifespan and delays the onset of age-related diseases across species [24]. One of the key mechanisms underlying the benefits of caloric restriction is the induction of mitohormesis, which enhances antioxidant defenses and mitochondrial biogenesis [9,20]. This hormetic process, mediated through pathways such as AMPK, SIRT1/3, and PGC-1α, ultimately contributes to improved metabolic health, reduced chronic inflammation, and protection against T2DM and cardiovascular complications [20,25,26].

Caloric restriction exerts its effects not solely through the reduction of energy intake but also by activating beneficial biological pathways. For example, under conditions of caloric restriction, increased mitochondrial activity leads to mild ROS production, which stimulates the endogenous antioxidant system without overwhelming it. The occurrence of this phenomenon is corroborated by human and animal studies demonstrating improvements in insulin sensitivity and reductions in pro-inflammatory signaling, including NF-κB suppression, as well as maintenance of genomic stability [24,27]. Notably, findings from the CALERIE randomized controlled trials consistently demonstrated that 6–24 months of moderate caloric restriction in healthy, nonobese adults lowered insulin levels and body temperature, reduced DNA damage, and improved oxidative stress and metabolic markers, supporting the role of moderate caloric restriction in slowing biological aging [27,28,29,30,31].

In model organisms, such as Caenorhabditis elegans, impaired insulin/insulin-like growth factor 1 signaling extends lifespan by promoting mild mitochondrial ROS production. Zarse et al. reported that this effect involves mitochondrial L-proline catabolism, which transiently increases ROS levels and activates protective pathways, providing a clear example of mitohormesis in the context of extended longevity [32].

Insights from starvation biology further suggest that mild caloric restriction may protect renal function by enhancing metabolic resilience [33]. Additionally, nutritional ketosis has been proposed as a complementary pathway that can induce mitohormesis and further enhance mitochondrial function, thereby reinforcing the protective metabolic adaptations observed during caloric restriction [11].

Collectively, these findings support the development of nutritional and pharmacological interventions that leverage mitohormesis for organ protection in T2DM.

4. Exercise Physiology and Mitohormesis

Regular physical activity is another well-established physiological trigger of mitohormesis. Moderate exercise transiently increases ROS production in skeletal muscles, thereby activating redox-sensitive transcription factors and endogenous antioxidant defenses through pathways involving Nrf2, MnSOD, catalase, and glutathione peroxidase [10]. This mild oxidative stress also induces an anti-inflammatory environment by upregulating cytokines such as IL-10 and suppressing pro-inflammatory mediators. Interestingly, IL-6, although widely recognized as a pro-inflammatory cytokine, can also act as a myokine during exercise, exerting context-dependent anti-inflammatory and metabolic effects [34].

Clinical and experimental studies consistently support that regular exercise improves insulin sensitivity, endothelial function, and organ stress markers, partly through adaptive redox modulation. Recent redox proteomics studies further emphasize that mild, localized ROS production is essential for optimal organ function. For example, mild ROS production can fine-tune proteins involved in energy metabolism. In brown fat, the ROS-dependent modification of uncoupling protein 1 (UCP1) enhances its heat-producing activity, showing how ROS signaling contributes to beneficial adaptations [35].

Importantly, activity-dependent hormetic effects depend strongly on the type, intensity, and duration of exercise. Although moderate, regular exercise promotes metabolic resilience and reduces the risk of cardiovascular and neurodegenerative diseases, excessive or unaccustomed inessential exercise can overwhelm antioxidant systems, leading to cellular damage and impaired recovery [36,37]. This duality highlights the importance of achieving an optimal redox balance to harness the protective effects of exercise-induced ROS.

Different exercise modalities may also influence the extent and quality of the hormetic response. For example, moderate aerobic training is recognized for its ability to increase mitochondrial biogenesis and MnSOD activity [38,39], whereas resistance training supports mitochondrial turnover and muscle quality in aging populations [40,41]. High-intensity interval training also induces transient oxidative stress, which, when appropriately dosed, further enhances endogenous antioxidant systems [42,43,44].

However, it is crucial to acknowledge that the excessive suppression of physiological ROS production can also be detrimental. For example, selenoprotein P, a liver-derived antioxidant protein, induces reductive stress in skeletal muscle, thereby inhibiting beneficial hormetic ROS signaling and reducing exercise endurance [45]. In brown adipose tissue, selenoprotein P-mediated ROS scavenging suppresses UCP1 activation by limiting Cys254 sulfenylation, consequently impairing thermogenesis [46]. These observations caution against the oversimplified view that indiscriminate antioxidant supplementation is always beneficial. As an example, a randomized human study demonstrated that the supplementation with vitamins C and E negated the exercise-induced improvements in insulin sensitivity and endogenous antioxidant defense [47]. These findings illustrate that oxidative and reductive stress can both disrupt the fragile hormetic window that is necessary for organ resilience.

5. Cellular Senescence, Senescence-Associated Secretory Phenotype, and Redox Balance

Cellular senescence is increasingly recognized as a substantial source of chronic oxidative stress and inflammation in aging and metabolic diseases [48,49]. Senescent cells maintain elevated levels of ROS production due to persistent DNA damage responses and mitochondrial dysfunction, which further sustain the senescence program through p53/p21 and p16INK4a pathways [50,51]. Lysosomal dysfunction is also a key hallmark of senescent cells, driving chronic senescence-associated secretory phenotype (SASP) activity and sustaining tissue inflammation. Our recent review summarized how impaired lysosomal integrity, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and defective autophagic flux collectively promote cellular senescence in cardiovascular tissues [6]. Through the SASP, senescent cells release pro-inflammatory cytokines, chemokines, and matrix-remodeling enzymes, thereby creating a pro-inflammatory microenvironment that promotes fibrosis and multi-organ dysfunction. Key SASP components include interleukins such as IL-6 and IL-8, chemokines like monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinases [49,52]. In metabolic organs such as adipose tissue and the kidney, the accumulation of senescent cells impairs regenerative capacity and exacerbates insulin resistance [53,54].

Recent evidence suggests that SGLT2 inhibitors may exert indirect senolytic effects. Katsuumi et al. demonstrated that SGLT2 inhibition reduces senescent cell burden and alleviates pathological aging in murine models [55]. Furthermore, SGLT2 inhibition may elevate ketone body levels, leading to mTORC1 suppression and reduced cellular senescence [23]. Ketone bodies may act as a double-edged sword, with protective and potentially deleterious effects depending on the context [23]. This potential senescence-modulating effect, combined with redox balance adaptation, may partially explain the multi-organ protective effects of SGLT2 inhibition that have been observed in clinical trials and real-world practice.

These findings highlight the complex interplay between mitohormesis and cellular senescence. Although mild ROS levels can activate protective pathways that delay senescence, excessive oxidative stress promotes senescent cell accumulation and chronic inflammation [9]. A comprehensive understanding of this duality is key to optimizing therapeutic strategies that target the Redox–Senescence–Organ Stress Axis in T2DM. Emerging strategies that combine senolytic agents with metabolic therapies aim to eliminate dysfunctional senescent cells while preserving beneficial adaptive responses such as mitohormesis [56,57]. Such integrative approaches might aid in disrupting the vicious cycle of oxidative stress, cellular senescence, and organ stress in T2DM, ultimately improving long-term cardiometabolic outcomes.

6. Inter-Organ Mitohormesis and Extracellular Vesicle Signaling

Recent advancements suggest that mitohormesis may extend beyond single tissues to encompass inter-organ stress signaling [9]. Crewe et al. demonstrated that energetically stressed adipocytes can release small extracellular vesicles (EVs) containing damaged mitochondria [58]. These EVs are taken up by distant cardiomyocytes, transiently elevating mitochondrial ROS levels and preconditioning the heart against ischemia–reperfusion injury. As illustrated in Figure 2, mildly elevated ROS levels in adipocytes promote the release of extracellular vesicles carrying mitochondrial components that can precondition the heart, whereas hypertrophic adipocytes with excessively elevated ROS levels release vesicles enriched in damaged mitochondria that exacerbate cardiac injury. This duality underscores the role of adipose tissue health in shaping inter-organ mitohormesis. This remarkable example of “inter-organ mitohormesis” broadens the concept of hormesis into a systemic adaptive response. At present, the clinical relevance of EV-mediated inter-organ signaling in T2DM remains conceptual, with evidence largely derived from preclinical models and limited human observational data; prospective, controlled clinical studies are needed to establish causality and therapeutic relevance.

Notably, 3-hydroxybutyrate enhances antioxidative gene expression in adipocytes, suggesting that ketone body metabolism may modulate inter-organ stress signaling through EV-mediated pathways [59]. Thus, metabolic interventions that alter ketone levels may influence the systemic redox balance by affecting EV cargo.

In the context of T2DM, adipose tissue dysfunction might dysregulate this EV-mediated crosstalk, shifting the balance toward chronic oxidative stress and inflammation across organs [58,60]. Conversely, therapeutic interventions that restore healthy adipose function, such as SGLT2 inhibitors, may help normalize EV signaling, potentially enhancing resilience through controlled inter-organ ROS signaling. Although direct evidence for SGLT2 inhibitors engaging this pathway remains limited, the conceptual parallel highlights the need for future research exploring whether these agents indirectly promote inter-organ mitohormesis, inherent to their multi-organ protective effects.

Beyond EVs, other mediators are also involved in inter-organ crosstalk. Although EVs offer a compelling mechanism for stress relay, inter-organ communication across the adipose–heart–liver–kidney–brain axis is not limited to EVs. Soluble factors—including adipokines (e.g., adiponectin), myokines (e.g., IL-6 in its exercise-induced anti-inflammatory role), hepatokines (e.g., fibroblast growth factor 21 [FGF21]), and cardiokines (e.g., growth differentiation factor 15)—as well as metabolites (e.g., ketone bodies, lactate, bile acids) and autonomic/neuroendocrine pathways can also modulate the redox and inflammatory status across organs. Conceptually, SGLT2 inhibitors may influence several of these channels indirectly via weight and adipose remodeling, natriuresis/hemoconcentration, blood pressure reduction, and ketone metabolism, thereby shaping systemic redox homeostasis without implying a single dominant route of action. For instance, adiponectin promotes mitochondrial biogenesis via p38 mitogen-activated protein kinase-mediated activation of PGC-1α in skeletal muscle [61]. Similarly, FGF21—primarily characterized as a hepatokine but also inducibly secreted from skeletal muscle (myokine) and adipose tissue (adipokine) under metabolic stress—enhances mitochondrial oxidative capacity by activating AMPK and SIRT1, leading to PGC-1α-mediated mitochondrial adaptation [62,63,64].

Emerging evidence also indicates that, apart from mitochondria, EVs transport microRNAs, proteins, and lipids that modulate redox balance in recipient tissues [65]. Such inter-organ vesicle-mediated crosstalk may have context-dependent effects: facilitating protective preconditioning in healthy states, whereas in metabolic disorders, it might exacerbate systemic oxidative stress and inflammation. Understanding how physiological or pharmacological interventions, including SGLT2 inhibitors and nutritional ketosis, modulate the cargo and destination of these vesicles might reveal new avenues for systemically targeting the Redox–Inflammation–Organ Stress Axis [11].

Future work should standardize EV isolation and cargo profiling, pair circulating signals with tissue-level readouts, and use stratified or crossover designs (e.g., SGLT2 inhibitor vs. glucagon-like peptide-1 receptor agonist [GLP-1RA] vs. their combination) to test whether EV cargo or soluble mediators track with redox biomarkers and organ-stress indices in humans.

As summarized in

Table 1. Comparative summary of redox-modulating strategies in T2DM.

Strategy	Primary Mechanism	Pros	Cons	Clinical Evidence
Antioxidant supplements	Direct ROS scavenging	Easy to administer	May suppress physiological ROS signaling	Lonn et al. [66]
Exercise	Induces mitohormesis	Improves overall health	Requires adherence	Radak et al. [10]
Caloric restriction	↓ mTOR, ↑ autophagy, ↑ mitohormesis	Reduces senescence	Long-term adherence difficult	Kume et al. [33]
Senolytics (experimental)	Eliminate senescent cells via targeted pathways	Targets the root cause of age-related tissue damage	Not yet widely available	Under investigation
EV-mediated signaling (conceptual)	Inter-organ redox communication via EVs	Explains systemic redox effects; potentially new therapeutic targets	Not yet a direct therapeutic intervention; needs more research	Crewe et al. [58]

EV, extracellular vesicle; mTOR, mechanistic target of rapamycin; ROS, reactive oxygen species; T2DM, type 2 diabetes mellitus; ↑, increase; ↓, decrease.

, various therapeutic approaches, such as exercise, caloric restriction, and senolytics, may exert beneficial effects on redox homeostasis by enhancing adaptive stress responses via hormetic mechanisms. In contrast, traditional antioxidant supplementation has shown limited clinical efficacy, likely due to the indiscriminate suppression of physiologic ROS signaling. EV-mediated inter-organ signaling represents a novel conceptual axis that may help explain systemic redox adaptation. However, its potential as a therapeutic target has yet to be validated.

7. Our Clinical Data: SGLT2 Inhibitors and Redox Adaptation

SGLT2 inhibitors are hypothesized to exert organ-protective effects through multiple mechanisms, including low-level mitochondrial ROS signaling that activates adaptive pathways, such as AMPK and NRF2, and suppresses the NLRP3 inflammasome (Figure 3). These processes may reduce inflammation, attenuate cellular senescence, and contribute to systemic resilience.

In our recently published investigator-initiated prospective study [67], treatment with an SGLT2 inhibitor significantly reduced albuminuria in patients with T2DM, while simultaneously lowering the serum levels of C-reactive protein and tumor necrosis factor receptors 1 and 2 (TNFR1/2). The reduction in albuminuria was positively correlated with the decrease in serum TNFR1 levels, suggesting that the anti-proteinuric effect may be partly mediated by anti-inflammatory mechanisms. These findings are consistent with emerging evidence that SGLT2 inhibitors may modulate lysosomal pathways, enhance autophagic flux, and suppress NLRP3 inflammasome activation [6].

Specifically, empagliflozin treatment was also associated with significant reductions in markers of subclinical organ stress, including cardio–ankle vascular index (CAVI), fibrosis-4 index (FIB-4), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels [68]. In our multivariate analysis, the reduction in CAVI was independently associated with empagliflozin use; the decrease in FIB-4 was related to changes in HbA1c, derivatives of reactive oxygen metabolites (d-ROMs), and TNFR2 levels, whereas NT-proBNP concentrations showed a trend-level association with urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) concentrations. These results suggest that, in addition to glycemic control, anti-inflammatory and redox-adaptive mechanisms may contribute to the organ-protective effects observed with SGLT2 inhibition.

As summarized in

Table 2. Overview of redox and senescence pathways in T2DM and their modulation by SGLT2 inhibitors.

Pathway/Factor	Role in T2DM	Effect of SGLT2 Inhibitors	Supporting Evidence
Mitochondrial ROS	Excess ROS promotes damage	↑ Adaptive ROS (mitohormesis)	Otoda et al. [68]
8-OHdG (urine/serum)	Marker of oxidative DNA damage	↑ (Suggests mitohormesis)	Otoda et al. [68]
d-ROMs	Reflects hydroperoxide levels	↑ (Mild oxidative shift)	Otoda et al. [68]
BAP	Indicates antioxidant capacity	↑ (Adaptive response)	Otoda et al. [68]
TNFR1/2	Markers of inflammation	↓ (Anti-inflammatory effect)	Otoda et al. [67]
Senescent cells (SASP)	Promote inflammation/fibrosis	↓ (Indirect senolytic effect)	Katsuumi et al. [55]
Ketone bodies	Metabolic signal, antioxidant role	↑ (With SGLT2 inhibitor use)	Tomita et al. [23]

8-OHdG, 8-hydroxy-2′-deoxyguanosine; BAP, biological antioxidant potential; d-ROMs, derivatives of reactive oxygen metabolites; SASP, senescence-associated secretory phenotype; TNFR1/2, tumor necrosis factor receptors 1 and 2; ↑, increase; ↓, decrease.

, SGLT2 inhibitors modulate multiple redox- and senescence-related pathways. In our study, we observed that while the levels of oxidative stress markers such as urinary 8-OHdG and d-ROMs increased following treatment, the biological antioxidant potential (BAP; a marker of antioxidant capacity) rose concurrently. This pattern may suggest an adaptive redox response consistent with the concept of mitohormesis; however, it cannot be excluded that elevated 8-OHdG levels also reflect unresolved oxidative DNA damage. Future studies incorporating complementary biomarkers, such as mitochondrial DNA deletions, will be needed to clarify the balance between adaptive signaling and persistent oxidative injury. The simultaneous increase in BAP indicates that the mild increase in ROS levels may have triggered endogenous antioxidant defense systems rather than causing net oxidative damage.

Interestingly, not only the use of SGLT2 inhibitors but also the concomitant use of a GLP-1RA emerged as an independent explanatory factor for the increase in urinary 8-OHdG levels in our multivariate analysis [24]. Although GLP-1RAs are known for their anti-inflammatory and modest antioxidant properties, they can paradoxically enhance mitochondrial respiration and mild ROS generation in certain metabolic contexts, potentially activating adaptive redox pathways consistent with the mitohormesis concept. Although GLP-1RA use emerged as an independent explanatory factor for elevated urine levels of 8-OHdG in our multivariate analysis, the possibility remains that concomitant therapies or unmeasured confounders contributed to this effect. The existence of this duality aligns with findings from recent experimental studies indicating that mild elevations of ROS levels may promote organ resilience rather than cause tissue damage. The interpretation of oxidative stress biomarkers, such as urinary 8-OHdG concentrations, in studies involving multiple metabolic agents must be approached cautiously because this study was limited by its relatively small sample size and the absence of a comparator arm without SGLT2 inhibitor use, which restricts the ability to draw definitive causal inferences. Moreover, we did not stratify patients by baseline oxidative stress levels or diabetes duration, which may influence redox responses, further limiting the generalizability of our findings.

Finally, any implication that SGLT2 inhibitors act through EV-mediated crosstalk should be considered hypothesis-generating. Mechanistic human studies are required before any clinical translation of this concept.

8. Conclusions

Our research highlights that SGLT2 inhibitors may contribute to maintaining redox balance, not only by suppressing oxidative stress but also by potentially engaging hormetic adaptations that upregulate endogenous antioxidant capacity. Although our clinical data suggest this effect, they do not definitively establish that SGLT2 inhibitors directly induce mitohormesis. Further mechanistic investigations are required to confirm this hypothesis and optimize redox-adaptive therapies for patients with T2DM. Recognizing oxidative stress as a modifiable signal—rather than merely a harmful byproduct—may drive a paradigm shift in diabetes care, targeting the root causes of multi-organ dysfunction through controlled redox adaptation. Future research should aim to clarify how these pathways interact with senescence biology and inter-organ crosstalk, ultimately enabling more precise, resilience-oriented diabetes care.

9. Clinical Implications and Future Directions

Figure 3 illustrates the proposed mechanism by which SGLT2 inhibitors induce mild mitochondrial oxidative stress and promote adaptive antioxidant responses, leading to reduced inflammation, decreased cellular senescence, and the protection of multiple organs in patients with T2DM. These observations caution against indiscriminate antioxidant supplementation.

While broad-spectrum antioxidant supplementation has largely failed to demonstrate clinical benefits, selective antioxidants targeting mitochondria, such as MitoQ, are under investigation. Preclinical and early clinical studies suggest that MitoQ may improve vascular function and protect against age-related oxidative damage, although its clinical utility in T2DM remains to be defined [69,70].

Controlled modulation of redox balance by encouraging mild ROS generation within a safe “hormetic window” may provide a novel strategy for preventing or delaying organ damage in T2DM [9,16]. Our findings regarding the effects of SGLT2 inhibitors align with geroscience principles that emphasize resilience building by targeting chronic inflammation, cellular senescence, and redox imbalance [71,72]. For clinicians, this perspective suggests that SGLT2 inhibitors might provide benefits extending beyond glycemic control by partially engaging adaptive redox pathways that preserve organ function. Notably, ketone body biology may represent an additional therapeutic axis in this context [73,74].

Future research should define the optimal thresholds of ROS modulation that maximize protective signaling without shifting into harmful oxidative overload. Additionally, studies should clarify how individual patient factors, such as baseline oxidative stress levels or senescent cell burden, modify responses to SGLT2 inhibitors. From a translational standpoint, EVs should currently be treated as a mechanistic model rather than a therapeutic target. The parallel evaluation of EVs and soluble mediators (adipokines, myokines, hepatokines, cardiokines, and ketone bodies) will be essential to disentangle their relative contributions to systemic redox adaptation in T2DM. Combining these agents with other hormetic interventions, such as structured exercise programs or mild caloric restriction, may further enhance resilience along the Redox–Inflammation–Organ Stress Axis.

These insights also underscore the potential utility of integrating redox biomarkers, such as urinary 8-OHdG, d-ROMs, and BAP, into routine clinical monitoring [75,76]. This approach might help identify individuals who demonstrate a favorable hormetic response profile and guide personalized intervention strategies. Ultimately, designing future trials that stratify participants by oxidative stress, inflammatory burden, and senescence markers will be critical for translating this concept into the clinical practice of precision metabolic medicine.