The core physiological function of IFN-γ, as a central cytokine of the Th1-type immune response, focuses on recognizing and defending against intracellularly parasitized viruses and malignant cells (22, 23) and has been established as a key mediator in the pathogenesis of AA. In the serum and lesion sites of AA patients, the upregulation of IFN-γ and TNF expression was positively correlated with disease severity and duration, especially in total/purple baldness and active AA (21, 24–26), which effectively promotes immune cell recruitment and exacerbates immune responses mediated by Th1 and natural killer (NK) cells by inducing the enhancement of chemokine expression (27), a cascade of biological events that severely disrupts the natural cycle of hair growth and the normal function of the hair follicle. Emerging evidence highlights IFN-γ’s critical involvement in AD. Stratification of AD patients according to IFNG expression levels and IFN-γ-secreting T cell capacity reveals two distinct subgroups: IFN-γ-high AD (exhibiting predominant endogenous AD characteristics) and IFN-γ-low AD (manifesting classical exogenous AD features) (28), which is consistent with previous studies (29, 30). Pathway analysis revealed that significant enrichment of gene sets associated with innate immunity, lymphocyte activation, inflammatory signaling, and immune system processes in the IFN-γ-high AD subgroup. IFN-γ and TNF-α bind to keratinocytes, induce apoptosis, and create a pro-inflammatory environment, leading to inflammatory skin lesions in AD. Meanwhile, IFN-γ also disrupts the skin barrier homeostasis by down-regulating the expression of FLG and mitogenin-1 and ceramide synthesis (31, 32). This barrier dysfunction facilitates inflammatory mediator release, creating a self-perpetuating cycle of immune activation and tissue damage.

In both AD and AA, a Th2-skewed immune response is observed (33), characterized by elevated levels of type 2 inflammatory cytokines, predominantly IL-4 and IL-13. IL-4/IL-13 can combine with type 1 cytokines (e.g., IFN-γ) to upregulate eosinophil-activating chemokines, including eotaxin-1 (CCL11) and eotaxin-3 (CCL26). These chemokines demonstrate significantly elevated expression levels in lesional AD skin (34), driving the recruitment of T lymphocytes, eosinophils, and basophils to the skin lesions. Furthermore, IL-4/IL-13 signaling downregulates key epidermal barrier molecules including FLG and involucrin, compromising tight junction integrity in the skin, whereas FLG gene mutations constitute the primary genetic determinant of epidermal barrier dysfunction (35), and also reduces ceramide synthesis and impairs corneal cohesion (20, 36, 37). The Th2 cytokine interleukin-4 disrupts normal stratum corneum cohesion in mice, providing implications for AD pathogenesis. Th2 cells are also shown to have a skewed cytokine homeostasis in patients with AA state. Specifically, IgE levels are significantly elevated in AA patients and this elevation is not dependent on the atopic state (38). At the same time, Th2-associated cytokines (IL-4, IL-13) also showed increased levels (39), and these cytokines may further promote T-cell infiltration into the skin and hair follicles, thereby triggering inflammatory responses and follicular damage (33, 40), and in the group of patients with AA combined with AD, the infiltration of Th2 cells around the diseased follicles was more prevalent. prevalent (14), and there was a significant correlation with IL-13 levels (41). In addition, it was further noted that enhanced activation of both skin-homing and circulating Th2 cells in AA patients versus healthy controls, with activation intensity directly correlating with clinical severity scores. Conversely, IFN-γ expression demonstrates stronger association with chronic disease progression (42).This observation aligns with the established immune trajectory of AD: The acute phase is predominantly characterized by a Th2 response, where IL-4/IL-13 signaling via the STAT6 (Signal Transducer and Activator of Transcription 6) pathway suppresses IFN-γ signaling. In contrast, the chronic phase exhibits significantly upregulated IFN-γ (43). This elevated IFN-γ can stimulate keratinocytes to produce CXCL10, which subsequently recruits cytotoxic CD8⁺ T cells to infiltrate hair follicles, ultimately triggering the autoimmune attack characteristic of AA. Thus, the Th2-to-Th1 immune shift occurring during the AD chronicity phase serves as a pivotal link connecting prolonged AD to AA pathogenesis.

Imbalances in the immune axis play a central role in the development of AD. Specifically, the increase in Th1/IFN-γ-associated products may not only signal a pro-inflammatory activation state of Th17/Th22 cells, but may also serve as a mechanism of counter-regulation of Th2 and Th17 activation (44, 45). Gittler et al. emphasized the strong association between the enhancement of this immune axis and the increase of immune activation in the progression of AD to the chronic phase, and this immune imbalance is already evident in the acute lesion stage (16), especially with a significant increase in Th22, Th2 and Th1-related products. Critically, IL-17 and IL-22, as key pro-inflammatory cytokines for Th17 and Th22 cells, exert pivotal roles in AD pathogenesis through distinct mechanisms. IL-22 upregulates gastrin-releasing peptide receptor expression in keratinocytes of the skin (46), which is key in mediating both non-histaminergic and pathologic itch (47, 48), thus affecting the itch symptoms in AD itch symptoms in patients. Simultaneously, Th17 cell activation in AD facilitates the generation of pro-inflammatory cytokines, which consequently might intensify inflammation and lead to alopecia (49, 50). In AA, perifollicular dermal infiltration by Th17 cells coincides with significantly elevated serum IL-17 levels compared to healthy controls, which is strongly correlated with the severity of AA (51). In addition, higher serum IL-17A levels in young AA patients may be associated with their increased susceptibility to psychological stress (52), and this susceptibility may stem from chronic stress-induced conversion of lymphocytes to Th17 responses (53). Therefore, adolescent-onset AA patients may portend a poor prognosis due to high IL-17A levels compared to those with advanced age onse (54). On the other hand, Atwa et al. observed that AA patients displayed elevated serum IL-22 levels compared to healthy controls, with a positive correlation with AA and depression duration (51, 55). These findings further support the critical role of immune imbalance in the chronic pathology of AD and AA.

The JAK (Janus Kinase) -STAT signaling pathway, as a core intracellular transduction mechanism for cytokines, critically regulating organism development, maintaining homeostasis, promoting cell proliferation and mediating immune responses. In the pathological process of AD, this pathway significantly affects keratinocyte function through JAK/STAT-dependent signaling of IL-4 and IL-13 (56). This dysregulation is demonstrated by suppressed FLG and endocannabinoid production, subsequently compromising skin barrier integrity (57, 58). Notably, STAT6 protein plays a central regulatory role in this signaling pathway, which not only upregulates the expression of the Th2-specific transcription factor GATA3 and regulates T cell proliferation and Th2 cell differentiation, but also promotes the conversion of immunoglobulin classes to IgE and IgG1 in B cells (59), which correlates with the fact that multiple STAT6 polymorphisms are associated with high levels of IgE and an increased AD susceptibility is closely associated with increased susceptibility (60). In addition, the STAT3 component of the JAK-STAT signaling pathway plays an amplifier role in the development of chronic itch (61), and its activation is directly associated with sustained itch signaling. Genome-wide association studies (GWAS) in AA patients have identified JAK-STAT pathway components—including STAT5A/B, STAT3, JAK1, and JAK3—as critical regulators of follicular cycling (62, 63). The up-regulated expression of these genes during the regression and resting phases, as well as their down-regulation during the early anagen phase, implies that JAK-STAT signaling may inhibit hair re-entry into the anagen phase (64). In contrast, JAK inhibitors have indeed demonstrated a significant ability to promote hair regrowth in clinical studies (65), as evidenced by elevated post-treatment hair keratin content, a reduction in perifollicular T-lymphocyte infiltration, and a significant down-regulation of inflammatory markers in the gene expression profile (66, 67).

OX40 and its ligand OX40L are both key members of the TNF superfamily. OX40 is primarily expressed on enhanced effector T cells (including Th1, Th2, Th17, and Th22 subpopulations) and regulatory T cells (Treg), while OX40L is primarily expressed on activated antigen-presenting cells (68). Ilves et al. found that OX40⁺ T cells were increased by 10-fold in the skin of AD patients compared to non-lesional skin (69). In the pathophysiology of AD, the OX40-OX40L signaling pathway plays a crucial role, promoting Th2 cell differentiation, These activated Th2 cells not only express OX40 but also release cytokines, further exacerbating damage to the epidermal barrier function. Preclinical studies in skin inflammation and asthma models further support that the OX40-OX40L signaling interaction is critical for the efficiency of regulatory responses in memory Th2 cells (70, 71). Additionally, this signaling pathway promotes the recruitment and proliferation of Th1, Th17, and Th22 cell subsets, which mediate keratinocyte proliferation, epidermal thickening, and T cell recruitment by upregulating the production of cytokines such as IFN-γ, IL-17, and IL-22 (72, 73). A study on mechanistic biomarkers demonstrated that blocking OX40 signaling not only regulates Th2 characteristics but also simultaneously suppresses Th1 and Th17/Th22-related immune activation (74). However, OX40 and OX40L are not significantly correlated with the clinical severity of AD. Additionally, Xiao et al. found that OX40 signaling significantly inhibits IL-17A production and Th17 differentiation in an experimental autoimmune encephalomyelitis model (75). The role of the OX40L/OX40 pathway in influencing Th cell fate remains to be further elucidated. Nevertheless, the activation of the OX40L/OX40 pathway, which promotes abnormal infiltration of effector T cells and cytokine release, may still be a key trigger for the disruption of follicular immune privilege. It is well known that mast cells (MCs) play a key role in various allergic diseases, including AD. Overactivation of the OX40L/OX40 pathway promotes Th2 cell proliferation, and the IL-4 secreted by these cells can induce B cells to differentiate into IgE-secreting cells. IgE binds to the high-affinity IgE receptor (FcϵRI) on MCs, leading to the release of histamine and IL-6, among other chemokines, which further recruit Th2 cells and eosinophils, exacerbating the immune inflammatory response (76). Additionally, mast cells upregulate OX40L expression due to IgE-FcϵRI cross-linking (77). Recent studies have further demonstrated that MCs are also involved in the pathogenesis of AA (78, 79). Specifically, compared with healthy control skin, the density of MCs in the dermis around lesions and hair follicles in AA patients is significantly increased. By releasing inflammatory mediators such as TNF-α and IL-6, they exacerbate autoimmune reactions, a phenomenon also observed in HF mesenchyme. This may indicate that Th2 cells act as an important bridge between AD and AA through the OX40L/OX40 pathway.

Meanwhile, Tregs also occupy a central position in the pathogenesis of AA (80), while OX40L on the MC surface can effectively weaken the immunosuppressive function of Tregs by interacting with OX40 on Tregs. This interaction leads to CD8⁺ T-cell hyperactivation, characterized by excessive IFN-γ and TNF-α production, alongside inflammatory cell recruitment (81, 82), while promoting the production of IgE by B cells as well as the release of Th2 cytokines (77), an interaction that disrupts the homeostasis between Tregs and CD8⁺ T cells and exacerbates the breakdown of immune privilege in AA hair follicles. Recent experimental studies have provided new evidence. Kim et al. found in a large-scale study of moderate-to-severe AA patients that the OX40L/OX40 axis was significantly upregulated in both the follicular surroundings and the circulatory system of patients, and this phenomenon was unrelated to atopic background. Additionally, the study observed an increase in OX40L⁺ antigen-presenting cells (APC) in the circulation, and non-skin-homing Tregs exhibited high OX40 expression, suggesting that at least part of Treg dysfunction may originate in the peripheral blood circulation prior to their migration to the skin (83). Therefore, the OX40/OX40L axis plays a key role in regulating inflammatory responses by modulating the interaction between Tregs and MCs. Abnormal activation of the OX40/OX40L pathway is not only a core driver of chronic inflammation in AD but also a critical link in the susceptibility of AD patients to AA. In AD, the sustained activation of this pathway sensitizes effector T cells and impairs Treg function, leading to an immune imbalance that directly disrupts the microenvironment necessary for maintaining follicular health. Thus, the activation of the OX40/OX40L pathway in AD is an important initiating factor in triggering the autoimmune process of AA. The OX40/OX40L axis, as a potential novel therapeutic target, may offer broad therapeutic benefits for patients with AA and AD comorbidity ( Figure 2 ).

Tralokinumab, the first-in-class monoclonal antibody targeting IL-13, was developed for AD. The drug modulates the expression levels of key AD biomarkers in the skin, restoring them to a near-nondiseased state, and effectively reduces the levels of systemic markers of Type 2 inflammation. In addition, a published case study showed that tralokinumab demonstrated significant efficacy in patients with severe AD accompanied by moderate to mild AA baseline severity AA scores (SALT of 22) (112), thus revealing its potential application in the treatment of comorbidities. Dupilumab, a monoclonal antibody targeting IL-4/IL-13 receptor signaling, has demonstrated significant efficacy in AD and AA, particularly in patients with an atopic backgrounds and elevated IgE levels (113–116). However, its therapeutic response in AA patients presents complexity. On the one hand, dupilumab is effective in improving symptoms in some AA patients; on the other hand, it has been reported that the drug may lead to worsening or new onset of AA (117). This two-sided response may be related to the immune skewed state of patients. In patients with Th2-skewed AA, dupilumab may bring positive efficacy through its inhibitory effect. Although dupilumab may ameliorate symptoms in AA patients with a Th2-skewed immune profile, it can paradoxically exacerbate hair loss in those with Th1-dominant AA, particularly among patients with low IgE levels (118–120). This differential efficacy stems from dupilumab’s dual immunomodulatory effects mediated through IL-4Rα blockade. In comorbid AD/AA characterized by Th2 skewing, dupilumab inhibits Th2 responses, effectively counteracting Th2-driven IgE elevation and barrier damage in AD, while also suppressing Th2 cell-mediated assistance to pathogenic CD8⁺ T cells in AA. Conversely, in Th1-skewed AA lacking significant Th2 activity (e.g., low IgE), dupilumab’s suppression of the Th2 pathway lifts the brake on the key negative feedback control normally exerted over the Th1/IFN-γ axis. This results in excessive amplification of IFN-γ signaling, which in turn promotes CD8⁺ T cell-mediated autoimmune attack on hair follicles, ultimately manifesting as worsened alopecia. In addition, gender differences also affect the efficacy of dupilumab in patients with AA. Studies have shown that female patients are more inclined to Th2 skewed disease, whereas males are more often associated with Th1 skewed disease. Thus, during treatment, female patients (Th2 skewed) are more likely to benefit from dupliyumab therapy, whereas male patients (Th1 skewed) may be at higher risk of deterioration (118). Stratified treatment strategy based on Th1/Th2 skewed status and IgE levels: preferred dopplerizumab for Th2 skewed (high IgE) patients; combined with JAK inhibitors or OX40L antagonists for Th1 skewed (low IgE) patients. Notably, although the prognosis of patients with dupilumab-induced AA worsening is usually favorable, and some patients even remit spontaneously, early recognition and intervention of AA worsening symptoms are crucial for timely adjustment of treatment regimens. Therefore, in clinical practice, physicians should fully consider patients’ immune skewed status and gender differences in order to develop individualized treatment plans and closely monitor changes in disease.

The JAK-STAT pathway is a key signaling pathway in the development of AD and AA, and JAK inhibitors have shown promising therapeutic efficacy by blocking the signaling of key cytokines in this pathway and suppressing inflammatory responses (121, 122). Compared with first-generation JAK inhibitors (e.g., ruxolitinib and baricitinib), second-generation JAK inhibitors (e.g., upadacitinib and abrocitinib) have demonstrated a significant increase in therapeutic efficacy and have been noted for their higher selectivity and excellent safety profile. In particular, upadacitinib has shown significant efficacy and favorable tolerability in managing comorbid AA and AD comorbidities (123, 124), and its therapeutic potential is particularly promising in AD patients who have failed to respond to or experienced side effects from dupilumab (125). In clinical practice, upadacitinib has not only brought new therapeutic hope to adolescent AA patients with mild AD, but also enabled certain patients with moderate-to-severe AD comorbid with AA, who demonstrated response to baricitinib but discontinued the drug due to side effects, to achieve skin lesion regression and scalp hair regrowth. Real-world evidence documents upadacitinib’s dual efficacy: adolescent AA-AD patients (12–17 years) achieved 80% hair regrowth by 6 months (Child-SALT ≤20), while baricitinib-intolerant adults showed 2.3-fold greater body surface area(BSA) improvement versus baseline (126, 127). Similarly, upadacitinib has shown positive therapeutic effects in adolescent cases of severe refractory AD combined with AA that failed to respond to treatment with dupilumab, as well as in AD patients with refractory AA (128, 129). Despite reports that AA may be induced after upadacitinib treatment for AD (130), the exact mechanism of this complication is not yet clear, and although the efficacy of JAK inhibitors as novel oral small molecule drugs, including baricitinib, upatinib, and abrutinib, is significant, the non-specificity of the mechanism of action raises additional safety consideration (131, 132). In summary, Overall, these findings imply that, as with AD, distinct clinical phenotypes and linked endotypes may characterize patients with AA. Emerging evidence demonstrates the therapeutic promise of second-generation JAK inhibitors (e.g., deuruxolitinib, brepocitinib) in AA-AD comorbidities, yet critical gaps persist in delineating their tissue-specific JAK-STAT pathway modulation and optimal dosing schedules, requiring validation through multicenter Phase IIIb trials coupled with longitudinal biomarker profiling ( Figure 4 ).

Rezpegaldesleukin, a novel biotherapeutic drug in clinical trials, works by specifically targeting the IL-2R complex to stimulate the proliferation of Tregs, thereby inhibiting the aberrant activation of pathogenic T-cell subsets and cytokine storm-mediated excessive immune responses. The drug is currently advancing into clinical studies in several immune-related disease areas and is currently in pivotal phase 2b trials for moderately severe AD and severe to very severe AA (133, 134). These studies will systematically evaluate the therapeutic potential of drugs in different immune disorder scenarios and provide evidence-based medical support for subsequent indication expansion. However, there are still challenges in the field of immunotherapy where efficacy has not met expectations, for example, a phase II study showed that for the treatment of AD, strategies targeting IL-17A in isolation had limited efficacy even in the hyper-activated state of Th17 (135), and that there was no significant difference in the treatment of AD for the anti-IL-22 monoclonal antibody compared to placebo (136). Similarly, no significant efficacy was observed for the anti-IL-17A drug suxinumab in patients with AA (137). In contrast, a variety of drugs targeting the OX40L/OX40 pathway are in phase II/III clinical development for AD treatment and show promise. For example, rocatilinimab has shown good efficacy at all four doses evaluated in its phase 2b trial, with sustained improvement up to 36 weeks post-treatment and efficacy maintained for 5 months after discontinuation. In addition, amlitelimab, by combining with OX40L and blocking its interaction with OX40, has shown rapid improvement in patients with moderate-to-severe AD, with a favorable safety profile, and efficacy was maintained for 6 months after discontinuation, both of which have demonstrated promise for AD treatment. Both demonstrate durable improvement in AD (138). OX40/OX40L inhibitors demonstrate compelling efficacy and favorable safety in AD treatment. Targeting this pathway concurrently depletes multiple pathogenic T-cell subsets (including Th1, Th2, Th17, Th22) and their memory counterparts. Given that aberrant interactions between OX40⁺ T cells and OX40L⁺ antigen-presenting cells (APC) also drive AA progression—a systemic inflammatory disease that may benefit from systemic OX40 inhibition regardless of atopic status—this approach holds therapeutic promise for AA. Although OX40L/OX40-targeted research in AA remains nascent, its potential warrants rigorous clinical validation. In light of these findings, future multicenter cohort studies are needed to clarify biomarkers of AD and AA comorbidity (e.g., OX40L serum levels, FLG mutation status) and to explore the synergistic effects and long-term safety of combination targeted therapies (e.g., JAK inhibitors ⁺ IL-4/IL-13 blockers) ( Table 1 ).