Regulatory Dynamics of Nrf2 With Sirtuins in the Brain: Exploring Cellular Metabolism, Synaptic Plasticity, and Defense Mechanisms

ABSTRACT

Nuclear factor erythroid 2–related factor 2 (Nrf2) plays a pivotal role as a transcription factor at the heart of cellular defense mechanisms against oxidative stress, orchestrating a suite of cytoprotective genes. This review places particular emphasis on the interplay between Nrf2 and Sirtuins—NAD⁺‐dependent deacetylases integral to redox regulation, metabolic control, and neuroprotection. We highlight how these proteins cooperate to regulate oxidative defense and cellular metabolism, with a particular focus on brain physiology and resilience. We briefly touch on the regulatory influence of specific microRNAs (e.g., miR‐126, miR‐34a) as emerging modulators of this pathway. Through this review, we aim to consolidate insights into Nrf2‐Sirtuin crosstalk, particularly in the context of brain health, and highlight potential therapeutic strategies including pharmacological agents, miRNA modulators, and ischemic preconditioning mimetics. This work aims to inspire further investigation and translational advances in the treatment of oxidative stress‐related neurological disorders.

Nuclear factor erythroid 2–related factor 2 (Nrf2) plays a pivotal role as a transcription factor at the heart of cellular defense mechanisms against oxidative stress, orchestrating a suite of cytoprotective genes. This review places particular emphasis on the interplay between Nrf2 and Sirtuins—NAD⁺‐dependent deacetylases integral to redox regulation, metabolic control, and neuroprotection. We highlight how these proteins cooperate to regulate oxidative defense and cellular metabolism, with a particular focus on brain physiology and resilience. We briefly touch on the regulatory influence of specific microRNAs (e.g., miR‐126, miR‐34a) as emerging modulators of this pathway.

Abbreviations

AD

Alzheimer's disease

AMPK

AMP‐activated protein kinase

ARE

antioxidant response element

ATP

adenosine triphosphate

CR

caloric restriction

CUL3

Cullin 3

DJ‐1

Parkinsonism‐associated deglycase

FPN1

ferroportin 1

GCL (γ‐GCL)

Gamma‐glutamylcysteine ligase

GSH/GSSG

Reduced/oxidized glutathione ratio

HO‐1

heme oxygenase 1

IPC

ischemic preconditioning

Keap1

Kelch‐like ECH‐associated protein 1

MAF (MafF, MafG, MafK)

small musculoaponeurotic fibrosarcoma proteins

MCAo

Middle cerebral artery occlusion

MEF

mouse embryonic fibroblast

MicroRNA

miRNA (e.g., miR‐34a, miR‐93, miR‐126)

NAD⁺

nicotinamide adenine dinucleotide (oxidized form)

Nampt

nicotinamide phosphoribosyltransferase

NF‐κB

nuclear factor kappa‐light‐chain‐enhancer of activated B cells

NQO1

NAD(P)H quinone dehydrogenase 1

Nrf1

nuclear respiratory factor 1

Nrf2

nuclear factor erythroid 2–related factor 2

NS‐OE

neuron‐specific SIRT1 overexpression

OS

oxidative stress

OS‐OE

oxytocin‐neuron‐specific SIRT1 overexpression

Oxt

oxytocin

PC12

pheochromocytoma cells (rat adrenal medulla cell line)

PGC‐1α

peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha

PKCε

protein kinase C epsilon

PPARγ

peroxisome proliferator‐activated receptor gamma

ROS

reactive oxygen species

RPC

resveratrol preconditioning

RSV

resveratrol

SH‐SY5Y

human neuroblastoma cell line

SIRT1–SIRT7

sirtuin family members 1 through 7

SQSTM1/p62

sequestosome 1

TBI

traumatic brain injury

TCA cycle

tricarboxylic acid cycle (Krebs cycle)

TLB

trilobatin

TNF‐α

tumor necrosis factor‐alpha

UCP2

uncoupling protein 2

1. Introduction

Oxidative stress presents a central role in various neuropathologies and in cerebrovascular disease. The imbalance created by the antioxidant response and the formation of reactive oxygen species places a major role in homeostasis maintenance and neuronal protection. Nuclear factor erythroid 2‐related factor 2 (nrf2) is a significant regulator in the antioxidant response and transcription factors related to the defense against reactive oxygen species (ROS). In addition, the Sirtuin family of NAD⁺‐dependent deacetylases (notably SIRT1 and SIRT3) has emerged as critical modulators of mitochondrial function, energy metabolism, and stress resistance. These two independent cellular routes seem to have some level of interplay and seem to share similar potential targets in various contexts. Our group has been at the forefront of investigating the molecular underpinnings of ischemic preconditioning (IPC), a neuroprotective phenomenon wherein brief episodes of sublethal ischemia confer resistance to subsequent, more severe insults, providing some degree of protection during ischemic stroke, suggesting the potential interaction of Nrf2 and the Sirtuins (Narayanan et al. 2018; Thompson et al. 2015, 2012). We have demonstrated that Nrf2 plays a central role in mediating IPC‐induced tolerance, particularly through its regulation of antioxidant defense pathways and mitochondrial function. Using both in vitro and in vivo models, we showed that IPC activates Nrf2‐dependent transcription of genes encoding cytoprotective enzymes, such as HO‐1 and NQO1, thereby reducing oxidative stress and improving neuronal survival following ischemic injury (Narayanan et al. 2015, 2018). In parallel, our studies suggest a convergence between SIRT1 and Nrf2 pathways, with resveratrol (RSV) serving as a metabolic enhancer (Khoury et al. 2018, 2019). Building on this body of work, one of the goals of this review is to explore the interplay between Nrf2 and Sirtuins in the brain and how this interaction may shape synaptic plasticity, metabolic homeostasis, and neuroprotection under conditions of oxidative stress (Figure 1).

FIGURE 1.

Summary of interactions from various stimuli with Sirtuins and Nrf2. (1) Show interactions with examples of an agonist of their respective Sirtuins. (2) miRNA interactions with Sirt1 and Sirt2. (3) Examples of pharmaceutical compounds that can regulate Sirtuins. (4) Environmental stimulus capable of regulating Sirtuins interaction with Nrf2. Green arrows show positive regulation of the various stimulus and downstream elements in the Sirt‐Nrf2 interaction. Red lines show elements that are negatively regulated by the Sirt‐Nrf2 interaction. Black lines show downstream elements that Nrf2 regulates and have a role in the regulatory pathways of the cell.

2. Nrf2 in Oxidative Stress: Mechanisms of Activation and Therapeutic Targeting

Oxidative stress (OS) is a key driver of neuronal damage in both acute and chronic neurological conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and traumatic brain injury (TBI). The transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2) plays a central role in the cellular defense against oxidative injury by regulating a wide array of antioxidative and cytoprotective genes. As a leucine zipper transcription factor, Nrf2 binds to antioxidant response elements (ARE) within the promoter regions of its target genes, initiating the transcription of detoxifying enzymes and antioxidant proteins (Moi et al. 1994; Liang et al. 2013). This signaling cascade significantly contributes to neuronal resilience across a range of neurodegenerative and cerebrovascular pathologies (Lastres‐Becker et al. 2016; Bahn et al. 2019; Narayanan et al. 2015).

Under basal conditions, Nrf2 is sequestered in the cytoplasm by Kelch‐like ECH‐associated protein 1 (Keap1), which serves as a substrate adaptor for the E3 ubiquitin ligase Cullin 3 (CUL3) complex. This complex tags Nrf2 for proteasomal degradation, limiting its availability and suppressing its transcriptional activity (Zhang 2006; Ganesh Yerra et al. 2013). However, in response to oxidative stress, specific cysteine residues on Keap1 become oxidized, resulting in the release and stabilization of Nrf2. Additional modulators such as p62/SQSTM1 and DJ‐1 (Parkinsonism‐associated deglycase) further disrupt the Nrf2–Keap1 interaction, enhancing Nrf's nuclear translocation (Ganesh Yerra et al. 2013; Niture et al. 2014; Kensler et al. 2007). Once in the nucleus, Nrf2 heterodimerizes with small MAF proteins (MafF, MafG, or MafK) and binds AREs to promote the expression of its downstream target genes (Table 1).

TABLE 1.

Summary of interaction of Nrf2 linked to sirtuin with high clinical relevance.

Sirtuin	Model of Appearance (In vitro or Animal Models)	Pathology	Localization	Specific Cellular Pathway	References
SIRT1	In vitro	Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, traumatic brain injury, cardiomyopathies, stroke, aging	Predominantly nuclear	Nrf2‐driven antioxidant pathway, synaptic plasticity, neuroprotection, mitochondrial biogenesis	Chen et al. (2022); Kawai et al. (2011); Kim et al. (2018); Li et al. (2021); Lu et al. 2020; Mei et al. (2022); Shi et al. (2019); Xue et al. (2016); Zhu et al. (2022)
SIRT2	In vitro	Alzheimer's disease (AD), neuropathic pain, oxidative stress‐related conditions	Predominantly cytoplasmic	Nrf2‐mediated antioxidant pathway, iron homeostasis, autophagy, inflammation	Zhang, Hong, et al. (2019); Dryden et al. (2003); Liu et al. (2019); Liu et al. (2022); Shi et al. (2021); Zhao et al. (2018); Zhao et al. (2021)
SIRT3	Animal Models	Intracerebral hemorrhage, ischemia/reperfusion injury, neuroprotection	Predominantly mitochondrial	Inflammation reduction through SIRT3/Nrf2/HO‐1 pathway, maintenance of mitochondrial health, reduction of oxidative stress	Dai et al. (2022); Gao et al. (2020); Gao et al. (2018); E. N. Kim et al. (2018); Zhu et al. (2022)
SIRT6	Animal Models	Ischemia/reperfusion injury, neuroprotection	Predominantly nuclear	Regulation of redox metabolism	Pan et al. (2016)

The activation of Nrf2 triggers an orchestrated antioxidant response that not only neutralizes ROS but also promotes mitochondrial function, metabolic adaptation, and inflammation resolution. This response has been shown to attenuate neuronal damage in models of AD, PD, ischemia, and cardiac injury, underscoring Nrf's broad neuroprotective potential (Chen et al. 2012; Chen and Maltagliati 2018; Yang et al. 2017; Yen et al. 2017; Huang et al. 2015; Narayanan et al. 2018). Moreover, Nrf2 activation correlates with preserved cognitive function in aging populations and transgenic models of AD such as 3xTg‐AD and 5xFAD mice (Bahn et al. 2019; Forner et al. 2021).

Because of its central role in redox regulation, the Nrf2/ARE pathway presents multiple targets for therapeutic intervention. Strategies aimed at modulating Nrf2 activity include influencing its expression, nuclear translocation, DNA binding, or protein interactions through pharmacological agents, natural compounds, or endogenous regulators such as miRNAs (Figure 1) (Duangjan et al. 2021; Mei et al. 2022; Chen et al. 2016; Yen et al. 2017; Chen and Maltagliati 2018; Hong‐Qiang et al. 2018; Liang et al. 2013). Notably, emerging evidence also implicates sirtuins—a family of NAD⁺‐dependent deacetylases—in modulating the Nrf2 pathway at various stages, suggesting a synergistic mechanism of antioxidative control (Liu et al. 2020; Yang et al. 2017). This intersection adds a layer of metabolic regulation to the redox response and positions Nrf2 as a promising target for enhancing neuroprotection via endogenous cellular machinery.

2.1. Sirtuins in Neuroprotection: Isoform Functions and Ischemic Tolerance

Sirtuins are a family of NAD⁺‐dependent deacetylases that regulate critical aspects of cellular metabolism, redox homeostasis, and genomic stability, with important implications for longevity and neuroprotection. In mammals, seven sirtuin isoforms (SIRT1–SIRT7) have been characterized, each exhibiting distinct subcellular localizations and specialized functions (Morris et al. 2011; Thompson et al. 2015).

SIRT1, the most extensively studied member, is predominantly nuclear but capable of cytoplasmic translocation, where it modulates gene expression, mitochondrial biogenesis, and synaptic plasticity (Table 1). SIRT2, localized mainly in the cytoplasm, plays roles in microtubule dynamics and cell cycle control. Mitochondrial isoforms SIRT3, SIRT4, and SIRT5 are essential for maintaining mitochondrial metabolism and detoxification of reactive oxygen species (ROS), supporting cellular resilience under metabolic stress. In contrast, SIRT6 and SIRT7, which reside in the nucleus, are involved in DNA repair, telomere maintenance, and ribosomal RNA transcription, contributing to genomic stability (Morris et al. 2011; Thompson et al. 2015).

Our group has extensively investigated the neuroprotective effects of sirtuins, particularly in the context of cerebral ischemia. We demonstrated that RSV preconditioning (RPC)—a pharmacological approach that activates SIRT1—confers significant protection against ischemic brain injury. In rodent models, RPC upregulates SIRT1 expression, promoting mitochondrial efficiency and reducing neuronal damage following ischemic events. This effect is mediated, in part, through the SIRT1–uncoupling protein 2 (UCP2) signaling axis, highlighting a key mechanism by which SIRT1 enhances mitochondrial function and neuronal survival (Thompson et al. 2015; Koronowski and Perez‐Pinzon 2015).

Further supporting this pathway, we found that the neuroprotective benefits of RSV are abolished in neuronal‐specific SIRT1 knockout mice, reinforcing the essential role of SIRT1 in mediating ischemic tolerance (Khoury et al. 2018). Notably, RPC induces a long‐lasting window of ischemic tolerance—lasting up to 2 weeks—through integrated nuclear and mitochondrial adaptations. These adaptations involve the epigenetic repression of energy‐consuming processes (e.g., transcription and synaptic activity) in parallel with the activation of energy‐generating pathways (e.g., glycolysis, TCA cycle, and oxidative phosphorylation), ultimately elevating baseline ATP levels and enhancing the brain's metabolic resilience to ischemic stress (Khoury et al. 2019; Thompson et al. 2015).

In addition to SIRT1, our studies have highlighted a protective role for SIRT5 in the setting of cerebral ischemia. As a mitochondrial desuccinylase, SIRT5 modulates metabolic enzyme activity to preserve mitochondrial function under stress. We discovered that activation of protein kinase C epsilon (PKCε) enhances the expression of nicotinamide phosphoribosyltransferase (Nampt), which increases mitochondrial NAD⁺ availability and activates SIRT5. This cascade supports desuccinylation of mitochondrial proteins, maintenance of respiratory complex activity, and protection against ischemic injury (Morris‐Blanco et al. 2016).

Together, these findings underscore the diverse and complementary roles of sirtuin isoforms in regulating neuronal metabolism, mitochondrial health, and stress adaptation. The SIRT1–UCP2 and PKCε–Nampt–SIRT5 axes represent promising therapeutic targets for enhancing endogenous neuroprotection and metabolic stability in the brain.

2.2. SIRT1 Crosstalk Might Modulate Nrf2 Activity in the Epigenetic and Metabolic Activity

Sirtuin 1 (SIRT1), a NAD⁺‐dependent type III deacetylase, orchestrates numerous cellular processes including chromatin remodeling, synaptic plasticity, and neuroprotection (Baldelli et al. 2013; Khoury et al. 2018, 2019; Morris et al. 2011; Lau et al. 2010; Nakahata et al. 2008; Yang et al. 2017; Kong et al. 2011; Kim et al. 2010; Michan and Sinclair 2007; D'Angelo et al. 2021; Michan et al. 2010). Functioning as a metabolic sensor, SIRT1 responds to fluctuations in NAD⁺ levels and intracellular energy demands by deacetylating key regulators such as histones and Nrf2 (Khoury et al. 2018; Morris et al. 2011). Evidence suggests that SIRT1 promotes Nrf2 activity through several complementary mechanisms: direct deacetylation of Nrf2, increasing its transcriptional capacity or enhancement of Nrf2 nuclear translocation. Examples of some mediations could be inhibition of Keap1‐mediated ubiquitination, which stabilizes Nrf2 and prolongs its activity in the nucleus (Niture et al. 2014; Huang et al. 2015).

Functionally, this crosstalk supports redox regulation and mitochondrial function. For example, SIRT's inhibition of p53 under oxidative stress enhances Nrf2 accumulation in the nucleus, amplifying the antioxidant response (Yoon et al. 2016). In macrophages, SIRT1 activates AMPK, which further reinforces Nrf2 signaling and antioxidant gene expression (Chen et al. 2016). These interactions underscore a key SIRT1–AMPK–Nrf2 axis that integrates energy sensing with oxidative stress defense, promoting resilience in neuronal and glial populations.

2.3. SIRT2 and Nrf2 Crosstalk are Related in Cytoskeletal Regulation, Cell Cycle, and Metabolites Regulation

Sirtuin 2 (SIRT2), primarily cytoplasmic, participates in regulating cell cycle progression, cytoskeletal remodeling, and oxidative stress responses (North and Verdin 2007; Dryden et al. 2003; Pandithage et al. 2008; Xu et al. 2021). In vitro studies using HEK 293T, Saos2, MEF, and HeLa cells have shown that SIRT2 interacts with cyclin‐dependent kinase 1 to regulate the G2–M phase transition and binds alpha‐tubulin to modulate cytoskeletal dynamics.

Although SIRT's interplay with Nrf2 is less well‐defined than that of SIRT1, emerging evidence suggests SIRT2 can modulate Nrf2 activation. Notably, SIRT2 contributes to Nrf2 dissociation from Keap1, promoting nuclear translocation and activation of downstream antioxidant genes (Zhang, Bi, et al. 2019; Zhang, Hong, et al. 2019; Lee and Johnson 2004; Sarikhani et al. 2018; Xu et al. 2021).

However, the relationship appears context‐dependent. In certain in vivo models using Sirt2⁻/⁻ and Sirt2⁻/⁻;Nrf2⁻/⁻ mice, as well as HepG2 cells, SIRT2‐mediated Nrf2 deacetylation was associated with reduced nuclear Nrf2 levels, leading to the downregulation of ferroportin 1 (FPN1) and altered cellular iron homeostasis (Yang et al. 2017). Conversely, NAD⁺ supplementation—which mimics SIRT2 activation—has been shown to increase Nrf2 mRNA and nuclear localization via a SIRT2–ERK signaling pathway, linking SIRT2 to a protective antioxidant response under stress (Zhang, Bi, et al. 2019; Zhang, Hong, et al. 2019; Sarikhani et al. 2018).

Taken together, these findings point to a dual regulatory role for SIRT2, which may either promote or restrain Nrf2 signaling depending on the cellular context and metabolic state. The interplay between SIRT2 and Nrf2 in redox control and ferroptosis regulation merits deeper investigation as a therapeutic target.

2.4. SIRT5: Mitochondrial Resilience and Emerging Redox Crosstalk

Sirtuin 5 (SIRT5) resides in the mitochondria and exerts its function primarily as a lysine desuccinylase, regulating enzymes critical for mitochondrial metabolism and cellular energy production. Although direct Nrf2–SIRT5 crosstalk in the brain remains understudied, insights from cancer biology point to potential regulatory overlap. In ovarian cancer, SIRT5 has been shown to enhance the Nrf2/heme oxygenase‐1 (HO‐1) pathway, contributing to improved ROS clearance and chemoresistance (Zhang, Bi, et al. 2019; Zhang, Hong, et al. 2019). Similar associations have been reported in lung adenocarcinoma and non‐small cell lung cancer, where SIRT5 and Nrf2 expression correlate with enhanced redox buffering and cell survival (Shouhan et al. 2024).

Though evidence in the CNS is sparse, both SIRT5 and Nrf2 independently support mitochondrial integrity and oxidative defense. SIRT5 contributes to ischemic tolerance, NAD⁺‐driven mitochondrial protection, and maintenance of respiratory chain activity (Khoury et al. 2019; Thompson et al. 2012), whereas Nrf2 governs the transcription of antioxidant and anti‐inflammatory genes. This converging functionality in redox regulation and metabolic adaptation suggests a potential axis of interaction, especially under ischemic or neurodegenerative conditions.

Future studies are needed to elucidate whether a SIRT5–Nrf2 feedback loop exists in neurons or glia. Uncovering such mechanisms could inform strategies to target mitochondrial health and oxidative resilience in stroke, Alzheimer's disease, and related disorders.

2.5. Metabolic Regulation by Nrf2‐Sirtuin Axis

As described above, our research demonstrated the protective nexus between RSV and SIRT1 activity in vivo using Sirt1⁻/⁻ knockout mice, whereas in vitro studies with rodent astrocyte cultures derived from wild‐type and Nrf2⁻/⁻ mice revealed that RSV amplifies nuclear NRF2 accumulation. This RSV‐induced interaction enhances cellular antioxidant defenses by promoting Nrf2 activity (Khoury et al. 2018; Narayanan et al. 2018, 2015). These findings support the idea that RSV can mimic molecular adaptations seen in endogenous protective mechanisms (Hong‐Qiang et al. 2018; Khoury et al. 2018; Nakahata et al. 2008; Narayanan et al. 2015; Xue et al. 2016).

Under hypoxia/reoxygenation conditions, RSV enhances the stabilizing effect of damage‐regulated protein 1 (DJ‐1) on Nrf2, increasing DJ‐1 expression and facilitating its interaction with SIRT1. This crosstalk reinforces Nrf2 stability and transcriptional activity, as demonstrated in vitro using H9c2 cells (Ali et al. 2021). Similar interactions between DJ‐1, Nrf2, and SIRT1 have also been observed in human‐derived SH‐SY5Y neuroblastoma cells, suggesting conserved protective roles across different systems (Im et al. 2012; Takahashi‐Niki et al. 2016; Liu et al. 2020).

Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), a central regulator of mitochondrial biogenesis, energy metabolism, and lipid oxidation, is also modulated by SIRT1. PGC‐1α amplifies the activities of both Nrf1 and Nrf2, forming a crucial axis for metabolic adaptation (Chen et al. 2022; Liang and Ward 2006; Rius‐Perez et al. 2020; Shaito et al. 2023; Supruniuk et al. 2017). The interaction between PGC‐1α and Nrf2 is particularly significant during periods of exercise or oxidative stress, where it facilitates mitochondrial biogenesis in response to increased ROS levels (Baldelli et al. 2013; Rius‐Perez et al. 2020; Chen et al. 2022).

Beyond SIRT1, SIRT2 has also been shown to modulate antioxidant metabolism. In PC12 cells, the SIRT2–Nrf2 interaction influences the GSH/GSSG ratio by regulating γ‐glutamylcysteine ligase (γ‐GCL) levels. Experiments involving NAD⁺ supplementation, particularly in combination with the SIRT2 inhibitor AGK2, demonstrated that SIRT2 is integral in elevating Nrf2 expression and promoting its nuclear localization (Mei et al. 2022; Zhang, Bi, et al. 2019; Zhang, Hong, et al. 2019).

Nrf2 also plays a role in metabolic adaptation to caloric restriction (CR). For instance, in murine models, SIRT1 promotes fat utilization under dietary restriction and enhances oxytocin (Oxt) production through Nrf2 activation. This metabolic shift was observed in mouse strains overexpressing neuron‐specific SIRT1 (NS‐OE) and Oxt‐neuron‐specific SIRT1 (OS‐OE) (Matsui et al. 2018). CR has been widely recognized for its potential to improve cognitive function and mitigate the risk of neurodegenerative diseases by enhancing neuroplasticity, reducing oxidative stress and inflammation, promoting autophagy, and improving overall metabolic health (Morris et al. 2011; Sharma et al. 2024).

Additionally, other sirtuins such as SIRT6, which are also linked to CR, interact with Nrf2 in regulating redox metabolism. In vitro studies with human mesenchymal stem cells have shown that the absence of SIRT6 increases susceptibility to oxidative stress and metabolic dysregulation, highlighting its role in maintaining redox balance via Nrf2‐related pathways (Table 1) (Pan et al. 2016).

2.6. Synaptic Plasticity Modulation by Nrf2‐SIRT1

Given the recent escalation in Alzheimer's disease (AD) incidence, emerging investigations have explored the manipulation of Nrf2 and SIRT1 as a potential strategy for improving neuroplasticity and mitigating cognitive impairments associated with AD (Table 1).

Vitamin D has shown beneficial effects in adult male models of AD by enhancing synaptic protein levels and correcting memory deficits through SIRT1/Nrf2 signaling. This action curtails oxidative stress‐related synaptic anomalies and reduces amyloid‐beta generation (Duangjan et al. 2021).

Similarly, pterostilbene, a natural phenol structurally related to RSV, is associated with antioxidant and anti‐inflammatory properties relevant to cardiovascular and cognitive health during aging. In male KM mice, pterostilbene increases SIRT1/Nrf2 expression, thereby improving neuroplasticity and reversing cognitive dysfunction (Table 1). This effect is attributed to the prevention of mitochondria‐dependent apoptosis via the SIRT1/Nrf2 interaction (Chen et al. 2016). Supporting these observations, additional studies have demonstrated that SIRT1‐mediated Nrf2 induction influences apoptosis and autophagy pathways in neuronal cells (Yen et al. 2017; Chen et al. 2022).

2.7. Neuroprotection Mediated by Nrf2‐Sirtuins

Although the previous section focused on neuroplasticity and cognition, this section highlights the broader neuroprotective mechanisms mediated by the Nrf2–Sirtuin axis across diverse neurological injury models, including stroke, I/R injury, and neuroinflammation.

Emerging pharmacological strategies leverage the protective synergy between Nrf2 and SIRT1. Pretreatment with compounds such as diosmetin, a flavonoid derived from citrus plants with anti‐inflammatory, anticancer, and neuroprotective properties, has shown significant protective effects in ischemia/reperfusion models. These include protection of PC12 cell lines and attenuation of cerebral ischemic damage in vivo (Mei et al. 2022; Chen et al. 2022).

Conversely, SIRT1 inhibition in astrocytic cell cultures leads to reduced cellular viability, impairing the PGC‐1α/PPARγ–Nrf2 pathway, which is essential for mitochondrial function and resistance to oxidative damage (Chen et al. 2022; Lennox et al. 2014). Natural extracts, such as those from Anacardium occidentale L. leaves, have been shown to enhance the SIRT1/Nrf2 pathway, providing protection against glutamate/H₂O₂‐induced oxidative toxicity (Duangjan et al. 2021).

Notably, certain microRNAs (miRNAs) act as negative regulators of the Nrf2–Sirtuin axis. For example, miR‐34a and miR‐93 downregulate both Nrf2 and SIRT1, thereby reducing cellular antioxidant capacity. Specifically, miR‐34a suppresses the SIRT1/PGC‐1α/Nrf2 axis, increasing vulnerability to oxidative stress and sensitizing cells to apoptotic or chemotherapeutic insults. In cardiac fibrosis and heart aging, inhibition of miR‐34 has proven to have a beneficial effect; similar results have been shown in the lung injury in cecal ligation and puncture. In addition, downregulation of miR‐93 utilizing antagomir mitigates the effects of ischemic stroke post perfusion linked to the Nrf2/HO‐1 pathway (Lennox et al. 2014; Kawai et al. 2011; Chen et al. 2020; Huang et al. 2014; Boon et al. 2013; Wang et al. 2016).

Beyond SIRT1, other sirtuin isoforms play critical roles in neuroprotection. In models of intracerebral hemorrhage, intermittent fasting has been shown to reduce inflammation through activation of the SIRT3/Nrf2/HO‐1 pathway, lowering TNF‐α and IL‐1β expression levels (Dai et al. 2022). The compound trilobatin (TLB), a known SIRT3 agonist, protects against ischemia/reperfusion injury during middle cerebral artery occlusion (MCAo) (Table 1) by stimulating both the TLR4/NF‐κB and Nrf2/Keap1 pathways (Gao et al. 2020). In PC12 cells, TLB activates the AMPK/Nrf2/SIRT3 pathway, countering oxidative stress and preserving mitochondrial integrity (Gao et al. 2018).

Similarly, SIRT6 has emerged as a neuroprotective factor in I/R injury. Its effects are significantly dependent on Nrf2 activity, emphasizing Nrf's central role in orchestrating cellular defense during cerebral ischemia and reperfusion injury (Fujita and Yamashita 2018; Zhang et al. 2017).

Together, these findings illustrate how targeting specific components of the Nrf2–Sirtuin network—whether through natural compounds, metabolic conditioning, or gene expression regulation—offers promising therapeutic potential for a range of neurodegenerative and ischemic disorders.

Furthermore, the upregulation of mitochondrial biogenesis—a process tightly linked to both SIRT1 and Nrf2 activity following RSV intake—is critical for maintaining synaptic plasticity and cognitive resilience, particularly in the face of high energy demands associated with neuronal signaling and cytoskeletal reorganization (Rius‐Perez et al. 2020; Shaito et al. 2023).

In murine models, another natural compound, berberine, an alkaloid known for its immunomodulatory, antioxidative, and cardioprotective properties, has been shown to alleviate neuronal cell death and cognitive decline following lipopolysaccharide‐induced inflammation, acting through the SIRT1/Nrf2 pathway (Chen et al. 2022).

Similarly, hyperbaric oxygen therapy has been reported to enhance SIRT1 and Nrf2 expression, correlating with improvements in postanesthetic memory impairments (Hong‐Qiang et al. 2018; Xue et al. 2016).

In conclusion, interventions targeting the SIRT1–Nrf2 axis have demonstrated significant potential in ameliorating cognitive dysfunctions arising from diverse pathological conditions. These strategies collectively promote key mechanisms involved in cellular plasticity, synaptic integrity, and memory resilience.

3. Conclusions and Future Directions

The intricate relationship between Nrf2 and Sirtuins encompasses a dynamic network of regulatory mechanisms extending beyond direct protein–protein interactions. Although SIRT1 frequently modulates Nrf2 via direct deacetylation, it also indirectly influences Nrf's ability to interact with transcriptional cofactors such as HO‐1, NQO1, and PGC‐1α, thereby shaping redox signaling and cellular stress responses (Imai et al. 2000; Liang et al. 2013; Lau et al. 2010). Both SIRT1 and SIRT2 play critical roles in regulating Nrf2 stability and transcriptional activity, particularly under oxidative stress, by enhancing nuclear translocation and protecting Nrf2 from ubiquitin‐mediated degradation by deacetylating the lysine residues, 588 and 591 for SIRT1; 509 and 508 for SIRT2. Interactions, SIRT1 promotes nuclear translocation of Nrf2 through deacetylation at K506, whereas SIRT2 has been reported to reduce Nrf2 stability via deacetylation at K588, potentially favoring cytoplasmic localization and proteasomal degradation. (Yang et al. 2017; Kawai et al. 2011; Chen and Maltagliati 2018; Clements et al. 2006; Huang et al. 2017; Lau et al. 2010; Niture et al. 2014).

Environmental conditions such as iron homeostasis can further impact this relationship. For example, SIRT2‐mediated deacetylation has been shown to reduce Nrf2 nuclear accumulation, favoring its cytoplasmic retention and degradation (Yang et al. 2017; Zhang 2006). These processes are also modulated by upstream mediators including the Keap1/CUL3 complex and by signaling proteins involved in nuclear shuttling, such as JNK‐C and ERK1/2, which are themselves regulated via Sirtuin‐driven deacetylation (Chen and Maltagliati 2018; Niture et al. 2014; Velichkova and Hasson 2005; Liang et al. 2013; Sarikhani et al. 2018; Yen et al. 2017).

Together, these converging mechanisms position the Nrf2–Sirtuin axis as a critical therapeutic target capable of reducing ROS overproduction, enhancing metabolic stability, and mitigating neuroinflammatory and neurodegenerative pathologies.

In summary, the Nrf2–Sirtuin network engages multiple layers of regulation—including epigenetic control, transcriptional fine‐tuning, and nuclear trafficking—to support oxidative resilience, energy homeostasis, and neuroprotection. These pathways offer tangible opportunities for therapeutic development, particularly through interventions targeting SIRT1, SIRT2, and their influence on Nrf2 dynamics. Small‐molecule activators, miRNA‐based strategies, and natural compounds such as RSV and pterostilbene represent promising translational avenues.

Looking forward, future research should focus on clarifying isoform‐specific regulation, particularly how SIRT1 modulates Nrf2 activity across distinct brain regions and under diverse physiological stressors. Additionally, further investigation into aging‐associated miRNAs, including miR‐34a and miR‐93, may uncover novel therapeutic opportunities to modulate the Nrf2–Sirtuin axis in the context of neurodegeneration. Continued pharmacological innovation—for instance, the refinement of SIRT1‐targeting agents like SRT1720 analogs with improved central nervous system bioavailability—could significantly enhance therapeutic potential. Moreover, exploring the role of Nrf2‐associated histone modifications may provide deeper insight into the epigenetic regulation of redox‐responsive gene networks.

As the field moves forward, it will be essential to assess Nrf2–Sirtuin interactions in diverse disease models and physiological conditions, whereas also integrating findings into clinical research frameworks. Personalized strategies that account for individual variability in Nrf2 or Sirtuin function may further improve therapeutic precision. Ultimately, advancing our understanding of this regulatory axis holds the promise to transform the treatment of neurodegenerative, ischemic, and metabolic diseases, bringing us closer to targeted, redox‐sensitive therapies tailored to patient‐specific biological profiles.

Author Contributions

Efrain J. Perez Lao: conceptualization, investigation, writing – original draft. Eric Fagerli: writing – review and editing. Fernando Ferrier: writing – review and editing. Juan I. Young: writing – review and editing. Miguel A. Perez‐Pinzon: writing – review and editing, writing – original draft.

Conflicts of Interest

The authors declare no conflicts of interest.

Perez Lao, E. J. , Fagerli E., Ferrier F., Young J. I., and Perez‐Pinzon M. A.. 2025. “Regulatory Dynamics of Nrf2 With Sirtuins in the Brain: Exploring Cellular Metabolism, Synaptic Plasticity, and Defense Mechanisms.” Journal of Neurochemistry 169, no. 9: e70193. 10.1111/jnc.70193.

Data Availability Statement

This review article does not report new datasets. All data referenced are from published literature cited within the manuscript. Further information is available from the corresponding authors upon reasonable request.