One of the key characteristics of AD is the compromised integrity of the skin barrier. The outermost layer of the skin, known as the epidermis, is rich in lipids, including cholesterol, cholesterol esters, ceramides, acyl ceramides, and free fatty acids. The outermost section of the epidermis, called the stratum corneum, consists of 15 to 25 layers of corneocytes. In this layer, surface proteins are cross-linked to ω-hydroxy ceramide, creating a lipid envelope around the cells. Beneath this, the stratum granulosum is the innermost layer of the epidermis. It contains secretory lamellar granules that release sphingomyelin, phospholipids, and glucosylceramides, which are then transported to other layers of the epidermis [18]. The skin’s stratum corneum typically contains ceramides, cholesterol, and free fatty acids. With a decrease in ceramide and lipid levels, the epidermal layer is weakened, and the transepidermal water loss (TEWL) increases [19]. Alterations in FLG and other structural proteins, such as loricrin, involucrin, keratins, desmoglein, and desmocollins, further disrupt the epidermal layer, as illustrated in Figure 1 [20]. The FLG gene, a crucial component in skin health, consists of two introns and three exons. A loss-of-function nonsense mutation in the FLG gene, located in the third exon, has a profound impact on the FLG protein. This mutation results in a reduction in the number of FLG protein copies, depending on whether the mutation is homozygous or heterozygous. The severity of the resulting phenotype is influenced by the position of the gene on the third exon and the number of copies of tandem repeats encoding the FLG protein [10]. A frameshift nonsense mutation in the Tmem79 gene disrupted the lamellar granule secretion process, leading to alterations in stratum corneum formation and a spontaneous dermatitis phenotype. This damaged barrier allows allergens, microbes, and irritants to enter, triggering an immune response [9].

During the early stages of AD, Th2-mediated cytokines, such as thymic stromal lymphopoietin (TSLP), IL-4, IL-5, IL-13, and IL-31, are elevated. As the disease progresses, acute lesions appear on the skin, resulting in an increased secretion of chemokines, including C-C motif ligand (CCL)-17 and CCL-22 [2]. These regulate and increase the production of IL-25 and IL-33, which are members of the IL-1 family. They further activate the ILC-2 and Th2 cells, where ILC-2 cells secrete IL-5 and IL-13, and the Th2 cells secrete the TSLP, IL-4, IL-5, IL-13 and IL-31 [21]. The cytokine superfamily, a key regulator of immune responses, governs various interactions between immune and non-immune cells, including keratinocytes, skin fibroblasts, and other cell types. Alarmins, a subset of cytokines, act as cytokine mediators or signalling molecules that activate immune responses by secreting TSLP, IL-33, and IL-25. Therefore, they act as central regulators of cutaneous immunity [22]. Children with AD show elevated oxidative stress markers, suggesting a disruption in the balance between oxygen and nitrogen radicals. Environmental pollutants, such as tobacco smoke and particulate matter, contribute to oxidative stress, causing inflammation and immune dysregulation. Oxidative stress activates the NF-κB pathway, which upregulates antioxidant enzymes but also induces proinflammatory cytokines (IL-6, IL-8, IL-9, and IL-33), thereby increasing dermal inflammation and worsening AD symptoms [23]. Fibroblasts, when the canonical NF-κB pathway is blocked by Ikkb gene deletion, exhibit a skin phenotype that closely resembles human AD-like skin lesions. These lesions are characterised by eosinophilia and a high number of type 2 immune cells. Our research reveals that skin fibroblasts, in addition to their traditional role in skin repair, play a critical regulatory role in immune homeostasis during early perinatal growth. They achieve this by modulating the activity of type 2 immune cells, a function regulated by Ikkb under normal physiological conditions [24]. These mechanisms have been illustrated in Figure 2. In the later stages of chronic AD, Th17 and Th22 cells are activated, suppressing the FLG expression, thus creating a disrupted skin barrier. The IL-4 and IL-13 also lead to the suppression of anti-microbial peptide formation, allowing microbes to enter the system. Both Th17 and Th22 cells actively secrete IL-22, which induces epidermal thickening, resulting in acanthosis, parakeratosis, and inflammation [25].

AD is characterised by an increased sensitivity to itch, including alloknesis and hyperknesis. Alloknesis is where harmless touch stimuli, like light touches from clothing, trigger itching sensations, while hyperknesis refers to an amplified itch response to stimuli that usually provoke itch [26]. IL-31 is known to cause itching directly and is found in elevated levels in the lesional skin and serum of individuals with AD. Neurons that express IL-31 receptor (IL-31R) indicate a notable role in the perception of itch. Nerve elongation factors (NEFs), such as nerve growth factor (NGF), facilitate the growth of nerve fibres, whereas nerve repulsion factors (NRFs), like semaphorin 3A (Sema3A), inhibit this growth. In healthy skin, NRF levels are higher than those of NEF, which helps maintain a balance and restricts nerve fibre infiltration into the epidermis. However, in the affected skin of AD, there is an increase in NEF levels relative to NRF, facilitating the penetration of nerve fibres into the epidermis. It implies that a careful balance between NEF and NRF regulates the density of epidermal nerves. Thus, a balance between NEF and NRF16 regulates epidermal nerve density [27]. External and internal itch-inducing substances interact with and activate various receptors on itch sensory neurons. When activated, these receptors, including cytokine receptors, G-protein coupled receptors, and transient receptor potential (TRP) channels, trigger action potentials. This activation leads to the immediate secretion of inflammatory substances, such as calcitonin gene-related peptide and substance P, highlighting the rapid response to itch-inducing substances [28].

AD is usually characterised by the dominance of a single species of microorganism, S. aureus. It has been reported in several studies that the presence of the bacterium S. epidermidis restricts the growth and colonisation of S. aureus. These bacterial colonies cause improper regulation of genes that play a role in epithelial barrier function, immune response, leukocyte movement, tryptophan degradation, and changes in metabolism [29]. Several studies also suggest that gut microbiota dysbiosis causes AD. The skin undergoes a process of renewal and turnover known as skin regeneration. After stem cells differentiate into epidermal cells, these cells undergo a process called keratinisation, which is governed by specific transcriptional mechanisms. The gut microbiome affects the signalling pathways that support epidermal differentiation, thereby impacting skin homeostasis [29]. Thus, this proves a correlation between gut microbes and skin health.

Repairing damaged skin is one of the most important goals in providing patient care in AD. Cocoa butter, shea butter, beeswax, olive oil, and grapeseed oil are a few natural alternatives for providing a physical barrier to the skin [30]. Daily usage of emollients reduces the dependency on TCS. Emollients, consisting of cholesterol, free fatty acids, and ceramides, are incorporated into lamellar bodies through topical administration, which enhances lipid synthesis and subsequent secretion into the intercellular lipid matrix. When compared with petrolatum-based occlusive moisturisers, an emollient containing a trio of lipids and a higher ceramide component (3×) was shown to promote hydration and decrease TEWL in AD patients. Honey, topical pre- and pro-biotics, thermal spring water, and vitamin E are a few natural alternatives to restore the skin and help in the growth of healthy microbiota [30, 31].

TCS are used as first-line treatment for mild to severe AD. TCS works by binding to and inhibiting the glucocorticoid receptors in skin cells. This action leads to the migration of these receptors to the nucleus, where they play a pivotal role in regulating the gene expression of key inflammatory mediators, such as prostaglandins and leukotrienes [32]. The downregulation of transcription factors such as NF-κB is a crucial part of this process, thereby decreasing the secretion of downstream pro-inflammatory factors. Low-potency TCS, moderate-potency TCS, high-potency TCS, and very high-potency TCS formulations are available. Low- or moderate-potency TCS, such as 0.05% fluticasone propionate or 0.1% hydrocortisone butyrate cream, are prescribed for daily application for approximately 4 weeks. Meanwhile, high- or very high-potency TCS, such as betamethasone propionate and clobetasol propionate, are usually recommended for application only twice a week due to the risk of atrophy. TCIs are also a safe anti-inflammatory therapy and are typically recommended if there is concern about adverse events. Antiseptics or antimicrobials are also recommended if skin infections are present, in addition to AD. Topical PDE4 inhibitor, crisaborole 2% ointment, is approved for use in patients 3 months or older with AD. Topical Janus kinase (JAK) inhibitor, ruxolitinib 1.5% cream, is used in patients 12 years or older [12]. Leukocyte cell-derived chemotaxin 2 (LECT2) has been implicated in the pathogenesis of several immune-mediated diseases. It plays a role in aggravating AD by downregulating skin barrier proteins and activating the NF-κB signalling pathway. Its modulation of inflammatory pathways identifies LECT2 as a potential therapeutic target in AD management, offering a ray of hope for future treatments [33]. Multiple metalloporphyrin-based superoxide dismutase (SOD) mimetics, such as MnTE-2-PyP⁵⁺ (BMX-010, AEOL10113), MnTnBuOE-2-PyP⁵⁺ (BMX-001), MnTnHex-2-PyP⁵⁺, and FeTnHex-2-PyP⁵⁺, have demonstrated the ability to improve oxidative stress and itch in preclinical models. Among them, BMX-001 and BMX-010 have advanced to stage 2 clinical trials [34, 35].

Anti-metabolites, such as methotrexate, are administered orally. Systemic corticosteroids, such as prednisone, cyclosporine A, and azathioprine, are also administered for shorter durations, as prolonged use carries a risk of side effects [36]. Systemic immunosuppressants are usually given to moderate to severe AD patients. In a phase 3 clinical trial, nemolizumab, an IL-31R antibody, was administered to pediatric patients (aged 6–12 years) for 16 weeks and was found to be effective against pruritus from day 2 onwards [11]. Dupilumab, an antibody targeting IL-4 and IL-13, and tralokinumab, an antibody targeting IL-13, are both Food and Drug Administration (FDA)-approved biologics currently available. Lebrikizumab (Ebglyss) is also a biological agent approved by the FDA in September 2024 for the treatment of moderate to severe AD. It serves as a target for IL-13, which causes inflammation, itching and skin damage. Adults and children above 12 years of age can take it [37]. Upadacitinib and abrocitinib are FDA-approved JAK-1 inhibitors recommended for use if other systemic therapies fail to work to manage chronic AD [38]. Systemic corticosteroids and anti-metabolites are generally less expensive than biologics or targeted therapies.

For treatment of flares and xerosis, topical or systemic therapy is given alongside phototherapy. Thus, it is considered a second-line therapy. Various types of phototherapies are UV A (UVA)/B phototherapy, narrow band UVB phototherapy, UVA1 phototherapy, and psoralen plus UVA (PUVA) phototherapy [17]. UVA1 phototherapy facilitates the apoptosis of Th cells, thereby reducing the secretion of pro-inflammatory cytokines, such as interferons. Phototherapy is usually recommended for adults over 12 years, considering the potential long-term risks associated with UV exposure. Studies have reported sunburn-like injuries and the dangers of skin cancers from prolonged exposure to UVA light. Also, the non-accessibility of phototherapy is a significant drawback. There is actually little evidence on different administrations of phototherapies [39]. Therefore, it is challenging to determine the most effective type of phototherapy currently.