The role of NRF2 transcription factor in inflammatory skin diseases

Abstract

The skin is the body's largest organ and performs several vital functions, such as controlling the movement of essential substances while protecting against external threats. Although mainly composed of keratinocytes (KCs), the skin also contains a complex network of immune cells that play a critical role in host defense and maintaining skin homeostasis. KCs proliferate in the basal layer of the epidermis and undergo differentiation, altering their functional and phenotypic characteristics. These differentiation steps are crucial for the stratification of the epidermis and the formation of the stratum corneum, ensuring the skin barrier's functions. Exposure to UV, environmental pollutants, or chemicals can lead to an overproduction of reactive species of oxygen (ROS), leading to oxidative stress. To ensure redox homeostasis and prevent damage resulting from the formation of ROS, the skin has an extensive network of antioxidant defense systems, mainly orchestrated by the nuclear factor erythroid‐2‐related factor 2 (Nrf2) pathway. Indeed, Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses inductions of pro‐inflammatory cytokine genes. In this context, Nrf2 is critical in preserving skin functions such as epidermal differentiation, regulating skin immunity, and managing environmental stresses. Besides, this pathway plays an important role in the pathogenesis of common inflammatory skin diseases such as allergic contact dermatitis, atopic dermatitis, and psoriasis. Therefore, the present review highlights the crucial role of Nrf2 in KCs for maintaining skin homeostasis and regulating skin immunity, as well as its contribution to the pathophysiology of inflammatory skin diseases. Finally, a particular emphasis will be placed on the therapeutic potential of targeting the Nrf2 pathway to alleviate symptoms of these inflammatory skin disorders.

Nrf2 is essential for maintaining skin homeostasis and regulating inflammation. This review highlights the multifaceted role of Nrf2 in skin inflammatory diseases like atopic dermatitis and psoriasis. While Nrf2 activation can be therapeutic, excessive activation can paradoxically exacerbate skin conditions.

Abbreviations

ACD

allergic contact dermatitis

AD

atopic dermatitis

AhR

aryl hydrocarbon receptor

ARE

Antioxidant Response Element

DMF

dimethyl fumarate

DNCB

2,4‐dinitrochlorobenzene

GSH

glutathione

HO‐1

heme oxygenase‐1

IL

interleukin

IMQ

imiquimod

KCs

keratinocytes

Keap1

kelch‐like ECH‐associating protein 1

NF‐κB

nuclear factor‐kappa B

NQO1

NAD(P)H quinone oxidoreductase 1

Nrf2

nuclear factor erythroid‐2‐related factor 2

PBM

photobiomodulation

PRRs

pattern recognition receptors

RNS

reactive nitrogen species

ROS

reactive oxygen species

SFN

sulforaphane

sMAF

small Maf proteins

TNF‐a

tumor necrosis factor‐alpha

UV

ultraviolet

1. INTRODUCTION

Keratinocytes (KCs), which are the most abundant cells of the epidermis, continuously communicate with immune cells residing in the skin through the production of soluble signaling molecules such as cytokines and chemokines to maintain cutaneous homeostasis. ¹ KCs have a dynamic response depending on the type of stimulation and can secrete various sets of cytokines and chemokines, including Interleukin (IL)‐1, IL‐20, and tumor necrosis factor‐alpha (TNF‐α) that can coordinate the skin inflammatory response whenever it is triggered. ² Indeed, inflammation of the skin is driven by various external stimuli, such as injuries, UV radiation, allergen uptake, microbial challenge, contact with irritants, or drugs, or it can be due to intrinsic, not always well‐defined, stimuli (e.g., mutations, autoantigens). The specific responses characterized by the kind of cytokines and immune cells involved and the extent of the reaction depend not only on the trigger but also on the individual genetic predisposition and daily lifestyle, including diet, alcohol consumption, and smoking. ³ , ⁴

There are two distinct forms of cutaneous inflammation: acute and chronic. Acute inflammation is a normal self‐limiting response to specific infectious agents, internal/external injury, chemicals, and UV exposure. The first step involves detecting danger signals, including pathogen‐ and damage‐associated molecular patterns (PAMPs and DAMPs) through numerous pattern recognition receptors (PRRs) expressed by the immune and non‐immune skin‐resident cells. In response to the recognition of these signals, PRRs activate downstream specific signaling cascades, resulting in the subsequent activation of nuclear factor kappa‐light‐chain‐enhancer of activated B (NF‐κB) and the inflammasome. These pro‐inflammatory pathways mainly culminate in the induction of several pro‐inflammatory cytokines, such as TNF‐α, IL‐1, IL‐6, and interferons (IFNs), as well as thymic stromal lymphopoietin (TSLP) and chemokines, including IL‐8, CXCL1, CXCL2, CXCL10, CCL2, and CCL20. The various secreted chemokines drive an influx of different types of immune cell subsets like neutrophils, monocytes, or T cells recruited to the site of inflammation, thereby promoting an effective immune response. ⁵ , ⁶ Acute inflammation aims to eliminate the causes of cellular damage, clear or absorb necrotic cells, and initiate tissue repair. However, a prolonged unregulated inflammatory response can lead to chronic inflammation continually causing tissue injury, commonly observed in many chronic dermatitis, such as atopic dermatitis (AD) and psoriasis. Many pro‐inflammatory signaling pathways are activated in the epidermis of patients with inflammatory skin disease, suggesting that KCs have a crucial role in shaping and regulating inflammation in the skin. ⁷ Accumulating evidence indicates that KCs play an active role in the pathogenesis of many, if not all, inflammatory skin diseases by highly interacting with immune cells, thus initiating or sustaining the inflammatory response. ⁸

Skin inflammatory diseases are often associated with redox abnormalities that must be regulated to ensure redox homeostasis within the cell and protect against inflammation. ⁹ To prevent oxidant damage, the skin possesses an extensive network of antioxidants, mainly orchestrated by the redox‐sensitive transcription factor nuclear factor erythroid‐2‐related factor 2 (Nrf2). ¹⁰ , ¹¹ Here, we review the significant roles of the Nrf2 signaling pathway in the pathophysiology of the most common inflammatory skin diseases such as psoriasis, AD, and allergic contact dermatitis (ACD). After an overview of the Nrf2 signaling pathway, we performed a literature review by exploring clinical and experimental studies that addressed the role of NRF2 expression and the effectiveness of therapies targeting the NRF2 pathway in both in vivo and in vitro settings.

2. SKIN AND REDOX STATUS

Skin homeostasis involves fine‐tuning its redox balance. Under physiological conditions, all types of skin cells produce, in a controlled manner, different reactive species, including the reactive oxygen species (ROS) and the reactive nitrogen species (RNS). ¹² , ¹³ Reactive sulfur species (RSS) have also been identified as omnipresent molecules in redox biology, playing pivotal roles in cellular functions and redox homeostasis. ¹⁴ The newly introduced concept of “skin redoxome” represents the cutaneous redox environment, including the generation of reactive species, their neutralization through antioxidants, and the signaling networks responsible for organizing the redox balance. ¹⁵ Since ROS and other highly reactive molecules—when produced at relatively low levels—are involved in fundamental cellular processes at steady state, redox homeostasis is essential to ensure skin biological functions. ¹⁶ The control of the balance between reactive species production and neutralization is thus crucial and is based on a wide range of detoxification systems. Besides, the skin, because of its strategic position, is particularly exposed to environmental aggressions. Integrating these different stresses by the tissue can lead to an imbalance state known as “oxidative stress.” In case of excessive stress, these detoxification systems can become overwhelmed and fail to maintain steady state control, resulting in an imbalance of the skin redox status.

Skin inflammatory diseases are often associated with redox abnormalities. Evidence shows increased markers of oxidative stress in psoriasis and AD patients, especially during AD exacerbation, as well as an altered antioxidant defense. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ Other studies reported an increased expression of reactive species producers such as inducible nitric oxide synthase (iNOS) in psoriatic skin lesions, ²² and an activation of myeloperoxidase and NADPH oxidase (NOX) in ACD. ²³ These findings suggest the involvement of oxidative stress in the pathogenesis and the development of several inflammatory skin diseases. ⁹ , ²⁴ Indeed, oxidative stress and inflammation are tightly related pathophysiological processes often present simultaneously in many pathological skin conditions. The inflammatory process constantly generates oxidative stress since reactive species are produced by cells involved in the host‐defense response, mainly the phagocytic cells. Oxidants, in turn, promote tissue inflammation either directly by inducing damage to biomolecules within the cell or the skin tissue, or by activating multiple pro‐inflammatory pathways, such as NF‐κB, mitogen‐activated protein kinase (MAPK), and janus kinase‐signal transducer and activator of transcription protein (JAK‐STAT) signaling pathways associated with the inflammatory response. ²⁵

Reactive species must be promptly detoxified to ensure dynamic redox homeostasis within the cell and protect against inflammation. To prevent oxidant damage, the skin possesses an extensive network of antioxidants, including antioxidant enzymes and non‐enzymatic antioxidants that inhibit, delay, or completely scavenge the action of free radicals and oxidants. ¹³ It is well established that the antioxidant response is mainly orchestrated by the redox‐sensitive transcription factor Nrf2, a key component regulating the inflammation signaling cascades and oxidative stress responses. ¹⁰ , ¹¹

2.1. The Keap1–Nrf2 pathway

Nrf2, encoded by the NFE2L2 gene, belongs to the mammalian cap‘n’collar (CNC) subfamily of basic leucine zipper (bZIP) transcription factors. Nrf2 is a master regulator of antioxidant gene expression in response to oxidative stress. ²⁶ It is also a cytoprotective transcription factor and could drive detoxification and excretion mechanisms of organic xenobiotics and toxic metals by regulating the expression of phase II enzymes. ²⁷ , ²⁸ Nrf2 is negatively regulated at the protein level through direct interaction with the dimeric cysteine‐rich, Kelch‐like ECH‐associating protein 1 (Keap1). ²⁹ The cysteine residues of Keap1 are important stress sensors and are targets for a range of chemicals and oxidants. The highly reactive cysteine residue, Cys‐151, senses mainly electrophilic compounds, including potent activators of Nrf2, such as sulforaphane (SFN) found in cruciferous vegetables and dimethyl fumarate (DMF). ³⁰ , ³¹ , ³² It is assumed that other cysteines, including but not limited to Cys‐273 and Cys‐288, also play a role in Keap1's ability to sense and respond to stress. ³³

Under normal basal conditions, Nrf2 primarily resides in the cytoplasm, where it forms a complex with Keap1. This association constantly leads to Nrf2 polyubiquitination through the Cullin 3 (Cul3)‐E3 ubiquitin ligase and addresses it to the degradation by the proteasome ³⁴ (Figure 1). Thus, Nrf2 is an unstable protein with a short half‐life of approximately 10–30 min and a high turnover, allowing for the maintenance of low basal levels of Nrf2 in normal conditions and providing a readily available pool of newly translated protein that can be rapidly stabilized in response to stress. ³⁵ Upon exposure to electrophilic chemicals or reactive species, modifications occur in the cysteine thiols of Keap1, disrupting the Keap1–Nrf2 complex, thus stabilizing Nrf2 ³⁶ , ³⁷ (Figure 1). While modification of Cys151 is thought to disrupt the Keap1–Cul3 interaction, other cysteines also play critical roles in Nrf2 regulation. Specifically, modification of cysteines, such as Cys‐288 within Keap1's Intervening Region (IVR), disrupts the Keap1–Nrf2 interaction via the “hinge and latch” mechanism. ³⁵ Modification of cysteines is thought to induce conformational changes in Keap1, hindering its ability to efficiently target Nrf2 for ubiquitination and degradation, thereby promoting Nrf2 accumulation (Figure 1). The accumulation of neo‐synthesized Nrf2 is further facilitated by its phosphorylation through various kinases, including PKC, CK2, PERK, CDK5, and MAPKs. These phosphorylations can increase Nrf2 stability and are context‐dependent, occurring under certain stimulation and/or in specific tissues. ³⁸ Phosphorylated Nrf2 subsequently migrates to the cell nucleus, where Nrf2 forms a complex with one of the small Maf proteins (sMaf) crucial for activating the transcription of Nrf2 target genes. ³⁹ , ⁴⁰ The Nrf2/sMaf complex activates the expression of approximately 200 genes by binding to a specific DNA binding motif known as antioxidant response element (ARE) ²⁷ , ³⁴ (Figure 1).

FIGURE 1.

Schematic representation of the Keap1–Nrf2 pathway under stressed or basal conditions. In unstressed conditions, NRF2 forms a complex with Keap1 through its DLG and ETGE motifs and subsequently undergoes ubiquitination by the Cul3‐E3 ubiquitin ligase complex, ultimately culminating in its degradation through the 26S proteasome pathway. Under oxidative or electrophilic stress, the cysteine residues within Keap1 are modified, and the activation of NRF2 can be initiated through two distinct proposed mechanisms. According to hinge‐and‐latch theory, the modifications of cysteine residues in the IVR region of Keap1, such as Cys‐288, lead to conformational changes that disrupt the binding of the DLG motif of NRF2 while keeping the ETGE motif intact with Keap1, making Cul3 inaccessible to cause ubiquitination, thus preventing the degradation of NRF2. In the Cul3 dissociation mechanism, Cys151, in particular in the BTB domain of Keap1, undergoes modification by electrophiles or oxidants, leading to the disruption of the Keap1–Cul3 complex, which prevents NRF2 ubiquitination. In both scenarios, preventing the degradation of the NRF2 pool causes an increased accumulation of the newly synthesized NRF2 molecules, which translocate to the cell nucleus. There, they engage with small Maf proteins (sMAF) and promote the transcription of NRF2 target genes through binding to antioxidant response element (ARE) sequences.

2.2. Downstream targets regulated by Nrf2 in the skin

While initially associated with oxidative stress, it is now widely recognized that Nrf2 responds to various stressors and participates in various biological processes. ²⁶ The expression of Nrf2 target genes is highly dependent on the levels of Nrf2 protein in the skin cells. Depending on the nature and intensity of the stimuli, Nrf2 can regulate the transcription of numerous target genes in a dose‐dependent manner. Nrf2 targets expressed under normal conditions are involved in mitochondrial physiology and biogenesis, proteostasis, and metabolic reprogramming as they regulate iron and heme metabolism. In contrast, stress‐induced Nrf2 targets are rather involved in antioxidant defense, xenobiotic detoxification, inflammation and immunity regulation, DNA repair, and prevention of apoptosis. ²⁶ , ⁴¹

To counteract the detrimental effects of reactive species in response to cellular stress, skin cells activate their antioxidant defense mechanisms, mainly coordinated by Nrf2 activity through AREs. Nrf2 induces antioxidant pathways by regulating the gene expression of a broad spectrum of antioxidant enzymes (Table 1) mainly involved in ROS neutralization, such as superoxide dismutase (SOD) and catalase, and in glutathione (GSH) synthesis and regeneration. ²⁶ , ³⁴ Additionally, the Nrf2‐mediated defense mechanism also involves the removal of potentially harmful xenobiotics through the activation of drug‐metabolizing enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1) and drug‐efflux transporters. ⁴² , ⁴³ , ⁴⁴ This process helps eliminate molecules that can generate ROS through redox cycling or deplete endogenous antioxidants by removing electrophiles. ⁴⁵ Overall, the coordinated gene expression mediated by Nrf2 forms a network of enzymes involved in xenobiotic detoxification and the elimination of pro‐oxidants, which helps maintain skin homeostasis, as detailed in Table 1. Several studies have linked a lack of antioxidant enzymes or alterations in their functions to inflammatory skin conditions, suggesting a key role for oxidative stress in both skin aging and the pathogenesis of chronic inflammatory skin diseases (Table 1). This dysregulation of the oxidoreductive balance can promote and exacerbate inflammation, contributing to conditions such as contact dermatitis, psoriasis, and even skin cancer. ⁹ , ²⁴ , ⁴⁶

TABLE 1.

Main antioxidant enzymes encoded by Nrf2 target genes, their principal function, ²⁶ , ⁴¹ , ⁴⁵ , ⁴⁷ , ⁴⁸ and their implications in inflammatory skin pathologies.

Antioxidant function	Nrf2 target enzyme (enzyme abbreviation)	Enzyme's principal function	Implication in inflammatory skin diseases or conditions
ROS neutralization	Superoxide dismutase (SOD)	Metalloenzyme that converts O2 •− into water and H2O2	Skin ulcer lesions (burn, wounds) 49 , 50 Allergic contact dermatitis to para‐phenylenediamine 51 Atopic dermatitis 21 , 52 Acne vulgaris 53 Skin cancer 54 Vitiligo vulgaris 55 , 56
	Catalase (CAT)	Converts H2O2 into water and oxygen	Skin aging 57 Atopic dermatitis 21 Psoriasis vulgaris 58 Vitiligo vulgaris 55 , 59
	Glutathione peroxidases (GPx)	Reduce H2O2 and lipid hydroperoxides using glutathione as a cofactor	Allergic contact dermatitis to nickel 60 Atopic dermatitis 21 , 52 Psoriasis vulgaris 58 Vitiligo vulgaris 55 , 61 Wound healing 50
	Peroxiredoxins (PRDX)	Reduce peroxides directly	Psoriasis 62 , 63 , 64
	Thioredoxin 1 (Trx1)	Reduces oxidized protein thiols and cleaves disulfide bonds	Allergic contact dermatitis 65 Irritant contact dermatitis 66 Psoriasis 67 UVB‐induced dermatitis 68
Electrophiles detoxification	NAD(P)H quinone oxidoreductase 1 (NQO1)	Reduces quinones and scavenges O2 •−	Irritant contact dermatitis 69
	Glutathione S‐transferases (GST)	Promotes the nucleophilic attack by glutathione on electrophilic molecules	Atopic dermatitis 70 , 71 , 72 Psoriasis 73
Glutathione production and antioxidant recycling	Glutamate‐cysteine ligase catalytic (GCLC) and modulator (GCLM) subunits	Catalyze the first and rate‐limiting step of glutathione biosynthesis	Psoriasis 74
	Glutathione synthetase	Catalyze the final step in glutathione biosynthesis	N/A
	Glutathione reductase (GSR)	Catalyzes the reduction of oxidized glutathione (GSSG) back to its reduced form (GSH) using NADPH as a cofactor	N/A
	Thioredoxin reductase 1 (TXNRD1)	A key enzyme responsible for reducing and regenerating oxidized Trx1 using NADPH	Allergic contact dermatitis to 1‐chloro‐2,4‐dinitrobenzene 75
NADPH regeneration	Glucose 6‐phosphate dehydrogenase (G6pd), 6‐phosphogluconate dehydrogenase (Pgd), isocitrate dehydrogenase 1 (IDH1), and malic enzyme (Me1)	Promote NADPH production through the pentose phosphate pathway, NADPH being a cofactor for both the GSR and the thioredoxin systems	N/A
Heme metabolism	Heme oxygenase‐1 (HO‐1)	Catalyzes heme degradation to carbon monoxide	Atopic dermatitis 76 Psoriasis 77

3. NRF2 FUNCTIONS IN THE SKIN

3.1. Role of Nrf2 in epidermal differentiation

According to the human protein Atlas, Nrf2 is ubiquitously expressed in all skin cells. ⁷⁸ Interestingly, Nrf2 also plays a role in promoting KC differentiation. Increased Nrf2 accumulation during calcium‐induced differentiation has been observed, and experiments with overexpressed Nrf2 in normal human KCs have shown enhanced expression of differentiation markers, such as loricrin and keratin‐10, even in the absence of calcium. ⁷⁹ The gradient of Nrf2 coincides with the apoptosis of KCs characteristic of the upper layers of the epidermis, particularly in response to ultraviolet (UV) radiation and other environmental factors. The higher expression levels of Nrf2 and the antioxidant enzymes in the skin's upper layers reinforce the epidermis antioxidant and detoxification capacity, especially as the superficial layers are more vulnerable to harmful external factors. ⁸⁰

3.2. Role of Nrf2 in barrier function

Nrf2 is a direct player in the epidermal barrier function, affecting desmosome stability, corneocyte fragility, and KC proliferation. Hyperkeratosis in the esophagus and forestomach of Keap1‐deficient mice was a cause of the malnutrition that resulted in their death. Biochemical data show that in the absence of Keap1, Nrf2 accumulates constitutively in the nucleus to stimulate the transcription of cytoprotective genes. Mating with Nrf2‐deficient mice reversed the phenotypic deficiencies in Keap1. ⁸¹

It has also been shown that transgenic mice with constitutively active Nrf2 exhibit a phenotype characterized by hyperkeratosis, epidermal thickening, and inflammation resembling lamellar ichthyosis. This phenotype is associated with upregulation of differentiation markers, including loricrin, involucrin, and keratin 10, together with impaired corneocyte desquamation, leading to hyperkeratosis. ⁸² Nrf2 may enhance skin barrier functions by activating specific genes in epithelial tissues in response to stress. For instance, Hebner et al. showed that the absence of Loricrin led to a delay in the formation of the epidermal barrier in utero in mice. However, this delay was alleviated by the activation of Nrf2. Additionally, members of the small proline‐rich protein 2 (Sprr2) gene family, particularly sprr2d and sprr2h, have been identified as direct downstream targets of Nrf2 through ARE sequences. ⁸³ Further investigations identified late cornified envelope 1 (Lce1) family members as target genes of Nrf2 that function in compensatory mechanisms to counteract the loss of loricrin. ⁸⁴

Moreover, high levels of hypo‐phosphorylated Nrf2 were found in lesional tissue of patients with pachyonychia congenita, a rare skin disease characterized by palmoplantar keratoderma and caused by keratin 16 gene mutations. This dysfunctional Nrf2 correlated with deficient synthesis of GSH in KCs. Conversely, topical application of SFN, a pharmacological activator of Nrf2, prevented clinical lesions and normalized redox balance in keratin 16 knockout mice, suggesting a potential role for Nrf2 in epidermal differentiation and skin integrity. ⁸⁵ In the same manner, previous research has shown that SFN can reprogram the expression of keratins 16 and 17, leading to the restoration of epidermal integrity in genetically modified mice with epidermolysis bullosa simplex. ⁸⁶ Indeed, Nrf2 can regulate the expression of keratins 6, 16, and 17, which are linked to KC hyper‐proliferation. ⁸⁷ Nrf2 also increases the expression of mi‐RNA 29 that targets desmocollin‐2, a major desmosomal component. ⁸⁸

Further insights into the role of Nrf2 in the skin barrier were obtained from studying mice with a loricrin gene deletion. Loricrin, a critical component of the cornified cell envelope, is vital in maintaining skin barrier function. In loricrin knockout mice, Nrf2 activation occurs in the epidermis, leading to the overexpression of Lce1 genes. These genes encode glycine/serine‐rich proteins similar in structure to loricrin, potentially compensating for loricrin deficiency. ⁸⁴ Recent findings have confirmed the coordinated action of Nrf2 and loricrin in ensuring the skin barrier cornification. In the absence of loricrin, the lack of sulfur‐rich proteins (thiols) in the epidermis disrupts the local redox balance, subsequently mobilizing the Nrf2 pathway to produce lamellar granules. ⁸⁹ Genetic activation of Nrf2 in KCs of a murine model of Netherton syndrome also improved the skin barrier defect by reducing the expression of pro‐inflammatory cytokines and upregulating the secretory leukocyte peptidase inhibitor (SLPI), which in turn inhibited kallikrein 7 and elastase 2 and increased the attachment of the stratum corneum by stabilizing desmosomes. ⁹⁰ This evidence underscores the role of Nrf2 in strengthening keratinization and promoting epidermal barrier cohesion.

The aryl hydrocarbon receptor (AhR) signaling pathway plays a critical role in breaking the vicious cycle of chronic inflammation by enhancing skin barrier function in atopic dermatitis, and this is linked to the Nrf2 pathway. At the molecular level, Nrf2 interacts with AhR, a transcription factor activated by specific chemical ligands such as dioxin and polycyclic aromatic hydrocarbons. AhR regulates the expression of phase I metabolism enzymes (e.g., cytochrome P450 (CYPs)) and proteins involved in epidermal differentiation (e.g., filaggrin, loricrin, involucrin). ⁹¹ The interaction between Nrf2 and AhR influences the barrier function, particularly under conditions of stress or in skin diseases characterized by an impaired skin barrier, such as AD or psoriasis. To date, active ingredients such as tapinarof (topical FDA‐approved treatment of psoriasis), coal tar, and glyteer (soybean tar) reportedly exert this dual benefit activity by inducing AhR–Nrf2 pathways. ⁹² , ⁹³ , ⁹⁴ , ⁹⁵

3.3. Role of Nrf2 in skin (photo‐)aging and photoprotection

The activation of the Nrf2 pathway has been found to protect against the acute effects of UVB and UVA radiation. ⁷⁸ Genetically modified mice with increased Nrf2 expression demonstrated resistance to UV‐induced erythema and the development of precancerous lesions and squamous cell carcinoma. Meanwhile, Nrf2 deficiency exacerbates the negative effects of UV radiation on the skin. ⁹⁶ , ⁹⁷ Nrf2 activators, like SFN or bixin, have also shown protective effects against UV‐induced erythema and pigmentation in clinical studies with humans. ⁹⁸ , ⁹⁹ , ¹⁰⁰

UV‐induced photoaging, characterized by dermal deterioration and the overproduction of matrix metalloproteinases (MMPs), is associated with oxidative stress. ¹⁰¹ The Nrf2 pathway offers advantages in this context by neutralizing ROS, reducing the “inflammaging,” ¹⁰¹ and alleviating fibrosis and metalloproteinase production. ¹⁰² , ¹⁰³ More pronounced photoaging effects, including wrinkles, induced by UVB in Nrf2‐deficient mice have also been reported. ¹⁰⁴ Molecular analysis has provided insights into the mechanisms by which Nrf2 provides photoprotection, including the modulation of antioxidant enzyme production, neutralization of toxic aldehydes, repair of oxidative DNA lesions, and inhibition of pro‐inflammatory cytokines. ⁷⁸ Considering these findings, Nrf2 activators are promising molecules for sun and after‐sun products. ⁹⁹ , ¹⁰⁵ Evidence from the 3D skin model demonstrates that the protection against UV‐mediated damage by using skin‐derived precursor cells is primarily mediated by the activation of the Nrf2/heme oxygenase‐1 (HO‐1) pathway via the phosphatidylinositol 3‐kinase/protein kinase B (PI3K/AKT). ¹⁰⁶ Interestingly, Nrf2 also plays a role in chronological skin aging, as observed in animal models for longevity. ¹⁰⁷ , ¹⁰⁸

Furthermore, Nrf2 activation may lower the risk of tumor initiation and promotion by reducing mutagenic DNA lesions and dampening UV‐induced inflammation. However, caution is necessary when modulating Nrf2 in cancer treatment, as cancer cells often rely on Nrf2 for survival and resistance to apoptosis. The hyperactivation of Nrf2 in cancer cells has been associated with aggressive proliferation, ¹⁰⁹ metastasis, ¹¹⁰ and resistance to chemotherapy. ¹¹¹

4. NRF2 AS A MASTER REGULATOR OF SKIN INFLAMMATION

In addition to the primary function of Nrf2 as a master regulator of xenobiotic detoxification and redox homeostasis within the cells, recent investigations revealed that Nrf2 also plays an essential role in the control of the inflammatory response. ¹⁰ , ¹¹² , ¹¹³ Persistent inflammation is a common characteristic of all pathophenotypes observed in the Nrf2 “diseasome.” ¹¹⁴ In particular, Nrf2 is a regulator of the skin inflammatory immune response, as several experimental studies have consistently demonstrated that Nrf2 deficiency is linked to enhanced inflammation. ¹¹⁵ , ¹¹⁶ , ¹¹⁷ Other data also support the role of Nrf2 in modulating the immune response. ¹¹⁵ Nrf2 inhibition in mice alters the phenotype of bone marrow‐derived dendritic cells. In fact, Nrf2‐deficient dendritic cells have impaired GSH levels, reduced phagocytic activity, enhanced expression of major histocompatibility complex (MHC) class II, and co‐stimulatory receptor expression of CD86 and CD80, thereby enhancing T cells stimulatory capacity. ¹¹⁸ Furthermore, Nrf2 disturbances have been implicated in chronic inflammatory skin diseases, such as psoriasis and AD. ¹¹⁹

Wound healing is a complex process involving KCs and Nrf2, particularly in managing inflammation and restoring homeostasis. Nrf2 activators have been reported as effective therapeutic approaches to promote wound healing. ¹²⁰ KCs regulate the initial inflammatory phase through a rigorously coordinated network of inflammatory signaling cascades, ¹²¹ while Nrf2 mitigates inflammation and reduces ROS levels after tissue regeneration. ¹²² However, the expression of key factors involved in wound healing was significantly lower in the early stages of wounds in Nrf2 knockout animals, leading to prolonged inflammation in the later healing phase. Interestingly, these changes in gene expression did not result in observable histological abnormalities. This normal healing rate would be partly due to the increased expression of Nrf3, a transcription factor that is a target of keratinocyte growth factor (KGF) and coexpressed with Nrf2 in healing skin wounds. ¹²³ Additionally, thioredoxin acts independently of glutathione to protect KC from oxidative damage. It compensates for the lack of glutathione, enabling KC to survive and thus maintain the skin's integrity and boost the healing process. ¹²⁴

Although Nrf2 deficiency prolongs inflammation, it does not severely impair the duration or quality of healing in non‐diabetic wounds. However, in diabetic animals, reduced Nrf2 expression leads to increased oxidative stress and apoptosis in the perilesional area of the skin, hindering wound healing. ¹²⁵ , ¹²⁶ Potent Nrf2 inducers like SFN, cinnamic acid, DMF, and triterpenoid RTA‐408 offer promising therapies for accelerating diabetic wound healing by counteracting these negative effects. ¹²⁷ Nrf2 signaling has also been shown to be a key event in physical plasma‐induced wound healing, promoting granulation and re‐epithelialization through a balanced antioxidant and inflammatory response. ¹²⁸ Furthermore, Nrf2 is suggested to stimulate the production of CCL2 chemokine by epithelial stem cells, which mobilizes macrophages, and in particular their secretion of epidermal growth factor (EGF), promoting keratinocyte proliferation and ultimately enhancing epidermal regeneration. ¹²⁹

Indirect mechanisms for counteracting inflammation involve the modulation of ROS and RNS by Nrf2. It is also appropriate to consider the role of Nrf2 in reducing inflammation by modulating redox‐sensitive key inflammatory pathways, including the Nod‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome and NF‐κB, ¹³⁰ and stimulating the expression of HO‐1, which has strong anti‐inflammatory and immunomodulatory properties. ¹⁰

5. IMPLICATION OF NRF2 IN SKIN INFLAMMATORY DISEASES

5.1. Nrf2 in allergic contact dermatitis

ACD is a delayed‐type hypersensitivity reaction that develops in two phases following skin exposure to an allergen. The initial sensitization phase, which is asymptomatic, occurs upon first contact of the skin with the allergen and is dose‐dependent. Subsequent re‐exposure to the same allergen initiates the elicitation phase, characterized by clinical manifestations appearing 24–96 h after contact. ¹³¹ , ¹³² , ¹³³ This reaction is mediated by cytotoxic CD8⁺ T cells and allergen‐specific effector CD4⁺ Th17 and Th22 cells. ¹³⁴ , ¹³⁵

Studies using mouse models of contact hypersensitivity demonstrate that Nrf2 regulates both the sensitization and elicitation phases of ACD. Exposure to the chemical sensitizer 2,4‐dinitrochlorobenzene (DNCB) induced a more severe inflammatory response in Nrf2‐deficient mice compared to wild‐type mice, highlighting Nrf2's protective role in ACD. ¹³⁶ Nrf2 plays a crucial role in chemical‐induced innate skin immunity, particularly during the sensitization phase, by modulating neutrophil recruitment and accumulation. ¹³⁷ Indeed, Nrf2 regulates chemokine production, such as CCL‐2, CCL‐4, and CCL‐11, and enhances macrophage phagocytosis, mainly via increased expression of CD36 scavenger receptor expression, a process independent of Nrf2's antioxidant function. The enhanced macrophage phagocytosis promotes efficient neutrophil clearance, and resolution of inflammation. ¹³⁷ Further supporting Nrf2's anti‐inflammatory role, another study showed that Nrf2 controls pro‐inflammatory cytokine production in human KCs exposed to cinnamaldehyde, a well‐known skin sensitizer. ¹³⁸

5.2. Nrf2 in atopic dermatitis

AD is a chronic, Th2‐driven inflammatory skin disease affecting a significant portion of the population. ¹³⁹ , ¹⁴⁰ Characterized by recurrent, itchy, eczematous lesions, AD is typically easily diagnosed clinically. ¹⁴¹ The disease is multifactorial, involving genetic predisposition, impaired skin barrier integrity, environmental exposures, and microbiome disruptions. ¹⁴² Defects in the filaggrin FLG and FLG2 genes, as well as in loricrin and involucrin, are the most common gene mutations associated with AD, resulting in altered envelope and moisturization issues. ¹⁴³ , ¹⁴⁴ Defective genes involving small proline‐rich protein 3 (SPRR3), tight junctions (CLDN1), and protease inhibitors (SPINK5) have also been noted in AD. ¹⁴² These gene mutations lead to a compromised skin barrier, allowing penetration of natural environmental allergens (e.g., house dust mites, pollens) and pollutants, which are reported to trigger AD exacerbations. ¹⁴⁵

Several research studies highlight the role of Nrf2 in the pathogenesis and treatment of AD. Loricrin deficiency in mice triggers Nrf2 activation, leading to overexpression of late cornified envelope 1 (Lce1) genes, which encode loricrin‐like proteins, likely compensating for the missing loricrin and restoring the redox balance disrupted by the lack of loricrin's sulfur‐rich components. These data confirm the coordinated roles of Nrf2 and loricrin in skin barrier integrity. ¹⁴⁶

Nrf2 has been shown to ameliorate AD‐like skin manifestations and type 2 immunity exacerbation through its antioxidant and anti‐inflammatory effects. ¹¹⁹ , ¹⁴⁷ A recent quantitative proteomics study identified a reduced Nrf2 activity and mitochondrial dysfunction in lesional and non‐lesional AD skin, together with a protein profile reflecting inflammation and impaired KC differentiation and epidermal stratification. ¹⁴⁸ In fact, the AD skin is subjected to oxidative stress, resulting in the repair‐associated type 2 immunity response ¹⁴⁹ and impaired Nrf2 activity due to physical damage in the epidermis. ¹⁴⁸ The former reflects the skin's attempt to recover from minor trauma, while the latter is associated with impaired tissue response and KC cell death in eczematous reactions. These data support the use of Nrf2 inducers, such as bixin (apocarotenoid) in the treatment of AD. ⁹⁹ , ¹¹⁹ Bioactive natural compounds have also demonstrated efficacy in reducing AD symptoms. For instance, Veronica persica extract (EEVP) improved the symptoms in a DNCB‐induced AD‐like mice model by decreasing inflammatory cytokine levels such as IFN‐γ, IL‐4, IL‐5, and IL‐13. It has also been demonstrated that EEVP has a high affinity for binding to Keap1, leading to Nrf2 activation, which in turn induces the expression of NQO1 and HO‐1. ¹⁵⁰ Similarly, ursolic acid, a triterpenoid compound found in plants, alleviated DNCB‐induced AD symptoms in mice, reducing dermatitis score and ear thickness, and inhibiting skin proliferation and mast cell infiltration. Ursolic acid was found to inhibit the Toll‐like receptor 4/NF‐κB pathway while simultaneously activating the Nrf2/HO‐1 pathway. ¹⁵¹ Phototherapies, including photobiomodulation (PBM) have demonstrated an ability to modulate immune responses and reduce oxidative stress markers. ¹⁵² , ¹⁵³ PBM, using low levels of visible red light (660 nm) or near‐infrared radiation (520 nm), effectively decreased TNF‐α, IL‐6, and IL‐8 mRNA expression while enhancing Nrf2 pathway activation in DNCB‐stimulated human KCs. ¹⁵⁴ This study highlights the Nrf2‐dependent anti‐inflammatory mechanism of PBM, suggesting its potential as a complementary AD treatment.

However, the role of Nrf2 in AD is complex. In a mouse model mimicking AD symptoms, short‐term pharmacological Nrf2 activation provided mild protection, but prolonged genetic activation of Nrf2 in murine KCs exacerbated skin inflammation, causing hyperkeratosis, epidermal thickening, increased KC apoptosis, DNA damage, and altered immune cell composition, highlighting the need for carefully controlled Nrf2 activation in AD treatment. ¹⁵⁵

5.3. Nrf2 in psoriasis

Psoriasis is a chronic skin disease affecting around 120 million people globally, with adult prevalence ranging from 0.2% to 2.3% depending on the region. ¹⁵⁶ Although classified as an auto‐inflammatory and autoimmune disease, its exact mechanism of development remains unclear. ¹⁵⁷ It is commonly accepted that environmental and internal factors, such as stress and Streptococcus infections, ¹⁵⁸ as well as physical injury ¹⁵⁹ and certain drugs such as beta‐blockers or lithium ¹⁶⁰ , ¹⁶¹ can trigger or exacerbate the psoriatic immune process in genetically susceptible individuals, particularly those carrying the human leukocyte antigen (HLA)‐class 1, HLA‐C*06:02 allele. ¹⁶²

The pathogenesis of psoriasis involves two main skin disruptions. On one hand, psoriasis is primarily driven by the dysregulation of the skin's immune barrier with a dense infiltrate of immune cells into the skin. It is well established that KCs are responsible for psoriasis early immune pathogenic events by producing autoantigens such as LL‐37 and keratin 17, initiating cutaneous inflammation. ⁸ , ¹⁶³ KCs also potentiate inflammation in response to stimuli or damage by activating both innate and adaptive immunity. It has been shown that KCs could induce the differentiation of T cells into Th1 and Th17 cells through direct cell–cell contact in the absence of antigen‐presenting cells. ¹⁶⁴ Furthermore, KCs amplify the inflammation through PRRs activation and the production of antimicrobial peptides and pro‐inflammatory cytokines and chemokines, such as IL‐1 family, TNF‐α, IL‐6, IL‐8, CXCL1, CXCL10, and CCL20. ¹⁶⁵ Innate immune cells also contribute to psoriatic inflammation by producing cytokines like TNF‐α, IL‐17, IL‐22, and IL‐23 that trigger KC proliferation, maintain a pro‐inflammatory environment, and lead to the subsequent T cell activation. On the other hand, psoriasis pathogenesis also involves physical barrier dysfunction arising from KC hyperproliferation (hyperkeratosis and acanthosis), incomplete KC differentiation in the stratum corneum, and disruption of intercellular junctions and the lipid‐rich matrix. ¹⁶⁶

The role of Nrf2 in psoriasis is controversial. Some studies suggest Nrf2 activation promotes KC hyperproliferation initially observed in HaCaT cells and later confirmed in a mouse model. In fact, HaCat cells stimulated by proinflammatory cytokines, IL‐17 and IL‐22, showed an increased Nrf2 accumulation and subsequent induction of keratin expression such as keratin 6, 16, and 17, contributing to hyperkeratinization that could be observed in psoriasis. Whereas in an IMQ‐induced psoriasis‐like mouse model, researchers found that inhibiting Nrf2 using small interfering RNA (siRNA) abolished the expression of keratins 6, 16, and 17, improving epidermal hyperplasia lesions. ⁸⁷ , ¹⁶⁷

Conversely, other evidence suggests a protective role for Nrf2 in psoriasis. The application of the Nrf2 activator, DMF, attenuates psoriatic lesions and restores epidermal differentiation in Nrf2 ^+/+ mice, an effect absent in Nrf2‐deficient mice. ¹⁶⁸ DMF's mechanism likely involves upregulating GSH and NQO1, and modifying Keap1 cysteine residues to activate Nrf2. ¹⁵⁷ , ¹⁶⁹ Other bioactive natural compounds have also shown promise in alleviating psoriasis. SFN is known to have anti‐inflammatory, antibacterial, and antioxidant properties. ¹⁷⁰ A study demonstrates SFN's therapeutic potential in preclinical models of inflammatory and autoimmune diseases, including IMQ‐induced psoriasis‐like mice and lupus‐like MRL/Lpr mice. Its observed effects, such as reducing inflammatory and autoimmune‐related cells and mitigating oxidative stress, suggest a possible mechanism involving Nrf2 activation, given SFN's known role as a potent Nrf2 inducer. ⁶³ Ma et al. have shown a deficiency of Nrf2 in the IMQ‐induced psoriatic mouse model. However, SFN seems to restore the expression of Nrf2 while decreasing keratins expression (K6/K16/K17), thus alleviating the psoriatic phenotype. ¹⁷¹ Moreover, galangin, an active flavonoid extract from Propolis, Alpinia officinarum and Alpina galanga, seems to have a therapeutic potential in psoriasis with anti‐inflammatory and antioxidant properties. ¹⁷² It has been shown that galangin promotes the Nrf2 pathway and attenuates oxidative damage and inflammation in rat's hepatic cells by increasing the expression of the antioxidative enzymes NQO1 and HO‐1. ¹⁷³ The 3H‐1,2‐dithiole‐3‐thione molecule (D3T) has also demonstrated an effective impact in reducing the thickening and scaling of IMQ‐induced psoriatic mice. ¹⁷⁴

5.4. Nrf2 in chloracne

Chloracne, a severe skin condition characterized by acne‐like eruptions and cysts, is often associated with exposure to halogenated aromatic hydrocarbons like dioxins. Interestingly, while Nrf2 activation is generally considered beneficial for the skin due to its antioxidant and anti‐inflammatory effects, excessive or prolonged Nrf2 activation can paradoxically contribute to skin pathologies resembling chloracne. Studies have shown that genetic and pharmacological Nrf2 activation in murine KCs induces pronounced acanthosis and hyperkeratosis, mimicking lamellar ichthyosis. ⁸² This is driven by Nrf2‐mediated overexpression of secretory leukocyte peptidase inhibitor (Slpi) and small proline‐rich protein 2d (Sprr2d). Although these proteins are typically associated with Nrf2's anti‐inflammatory function, their upregulation also causes cornified envelope instability and interferes with corneocyte desquamation. Furthermore, sustained Nrf2 activation in the skin can lead to sebaceous gland hypertrophy, seborrhea, and follicular hyperkeratosis, ultimately resulting in dilated infundibula, hair loss, and cyst formation—a phenotype similar to that observed in chloracne. ¹⁷⁵ This is attributed to increased expression of Nrf2 target genes, particularly epigen (a growth factor), Slpi, and Sprr2d. These proteins are also upregulated by dioxin in human KCs in an Nrf2‐dependent manner, further implicating Nrf2 in chloracne pathogenesis. The pathogenesis of dioxin‐induced chloracne involves activation of the AhR‐cytochrome P450 1A1 (CYP1A1) system, oxidative stress generation, and hyperkeratinization of KCs and sebocytes. ¹⁷⁶ , ¹⁷⁷ Importantly, a reciprocal relationship exists between AhR and Nrf2, involving both direct and indirect interactions. Nrf2 can directly bind to the AhR promoter, increasing AhR mRNA transcription, while AhR can bind to an XRE within the Nrf2 promoter, enhancing Nrf2 mRNA transcription. ¹⁷⁸ , ¹⁷⁹ Indirectly, AhR ligands metabolized by AhR‐induced CYPs generate oxidative stress intermediates, subsequently activating Nrf2. ¹⁸⁰ , ¹⁸¹ In Yusho patients intoxicated with high dioxin levels, the cinnamaldehyde‐containing Kampo herbal medicine has shown efficacy in improving chloracne, likely by activating the Nrf2 pathway and inhibiting AhR‐CYP1A1 signaling, highlighting the complex interplay between these pathways in skin pathologies. ¹⁸²

6. CONCLUSION

The skin, a complex organ composed predominantly of KCs, relies on an intricate network of immune cells and signaling pathways to maintain homeostasis and defend against external threats. KCs play a dual role, forming the physical barrier and actively participating in the skin immune responses. Disruptions to this delicate balance, whether due to genetic predisposition or environmental aggressions, can contribute to inflammatory skin conditions like ACD, AD, and psoriasis. As described in the present review, the transcription factor Nrf2 emerges as a critical player in skin health and disease. It orchestrates antioxidant responses, detoxifies harmful substances under stressful conditions, modulates epidermal differentiation, and regulates the skin immune function. Nrf2 deficiency is frequently associated with pathological inflammatory states and increased vulnerability to stressors, while Nrf2 activation, through natural or synthetic compounds, offers promising therapeutic potential for mitigating inflammation and alleviating symptoms in various skin inflammatory disorders. However, the complex and context‐dependent nature of Nrf2 highlights a crucial aspect: while generally beneficial, excessive Nrf2 activation can paradoxically induce chloracne‐like pathologies due to the upregulation of some of its target genes. Therefore, further research is needed to fully understand these mechanisms and develop safe and effective Nrf2‐targeted therapeutic strategies. Carefully titrating Nrf2 activity would maximize therapeutic benefits while minimizing risks.

FUNDING INFORMATION

This work was supported by a grant from the ANRT (Association Nationale de Recherche et de Technologie).

Salman S, Paulet V, Hardonnière K, Kerdine‐Römer S. The role of NRF2 transcription factor in inflammatory skin diseases. BioFactors. 2025;51(2):e70013. 10.1002/biof.70013

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.