Role of the STAT3 Signaling Pathway in Cell Proliferation and Inflammation in Psoriasis and Approaches for Targeted Therapies: A Review

Introduction

Psoriasis is a chronic inflammatory skin disorder primarily characterized by erythematous plaques and scaling. Its global incidence has continued to rise, making it a significant public health concern [1]. The STAT3 signaling pathway is a key branch of the JAK-STAT pathway. With STAT3 as the core effector molecule, it is translocated into the nucleus through JAK-mediated phosphorylation to regulate the transcription of target genes, mediating cell proliferation, anti-apoptosis, and secretion of inflammatory factors. Its continuous activation is one of the core molecular mechanisms underlying the pathogenesis of psoriasis, and recent studies have identified the STAT3-signaling pathway as a central player in the immune regulation and inflammatory response of psoriasis [2,3]. This pathway governs the abnormal proliferation and differentiation of keratinocytes and simultaneously modulates the expression network of key cytokines such as interleukin 17 (IL-17) and interleukin 23 (IL-23), thereby driving psoriatic pathology [4]. Notably, continuous STAT3 activation forms a pro-inflammatory feedback loop, potentially contributing to the chronicity of psoriasis [5]. Understanding the detailed molecular mechanism of STAT3 in psoriasis pathogenesis aids in uncovering disease etiology and offers theoretical guidance for developing new biological agents targeting the Janus kinase (JAK)-STAT signaling pathway, which is a classic intracellular signaling pathway that mediates cytokine and growth factor signals. With JAK and STAT as its core components, it regulates cell proliferation, inflammation, and immune responses through a phosphorylation cascade. Abnormal activation is closely associated with autoimmune diseases and inflammatory disorders) [6], and STAT3-targeting specific inhibitors have shown promising preclinical efficacy. However, challenges such as enhancing targeting specificity and reducing adverse effects remain [7].

STAT3 is a core component of the JAK-STAT signaling cascade and plays an essential role in cell proliferation, differentiation, apoptosis, and immune regulation [8,9]. Under normal circumstances, STAT3 activation is tightly regulated and has short-lived activity [10–12]. However, in psoriatic lesions, STAT3 remains continuously activated, serving as a key molecule driving disease progression [13]. Studies have shown that the STAT3 expression and phosphorylation level in psoriatic skin significantly increase and are positively correlated with disease severity [14]. Abnormal STAT3 activation not only directly promotes keratinocyte proliferation but also participates in key immune processes such as T helper 17 cell (Th17) differentiation and IL-17 production, thereby forming and maintaining the inflammatory environment of psoriasis [14,15]. Zhang, Ning et al [16,17] summarized the role of the JAK2/STAT3 signaling pathway in psoriasis, and recent reviews have provided new insights into the functions of this pathway in multiple cell types. Therefore, this article aims to review the regulatory role of the STAT3 signaling pathway in cell proliferation and inflammatory responses during psoriasis pathogenesis, and the latest progress in STAT3-targeted therapeutic strategies.

Molecular Mechanism of the STAT3-Signaling Pathway

THE ABERRANT REGULATORY MECHANISMS OF STAT3 IN PSORIASIS:

Psoriasis onset involves complex cytokine networks regulating STAT3 activity. Key drivers such as IL-6, IL-21, IL-22, and IL-23 activate the JAK-STAT3 pathway via their receptors [12,21,22], with the IL-23/IL-17 axis playing a central role: IL-23-driven STAT3 activation promotes Th17 differentiation and IL-17 production; IL-17 then acts on keratinocytes to release more inflammatory factors, creating a positive feedback loop that amplifies inflammation [23,24].

Recent studies have revealed that micro-ribonucleic acids (microRNAs) play a crucial role in the regulation of STAT3. For instance, miR-21-3p is significantly overexpressed in the skin lesions of patients with psoriasis [25]. It can directly target STAT3 and enhance its activity, thereby promoting the proliferation of keratinocytes and inhibiting their apoptosis [26]. In a mouse model, the expression of miR-155 was elevated, which inhibited suppressor of cytokine signaling 1 (SOCS1), a negative regulatory factor in the JAK-STAT pathway, enhancing the STAT3 signal [27].

The continuous activation of STAT3 is also influenced by epigenetic regulation. A study found that the chromatin openness of the promoter regions of STAT3 target genes in psoriasis lesions increased, which enhanced the binding ability of STAT3 to these regions, thereby improving the transcription efficiency of downstream genes [28,29]. This epigenetic alteration may be one of the important factors contributing to the chronicity and recurrence of psoriasis [28,29].

THE CORE ROLE OF STAT3 IN THE PATHOGENESIS OF PSORIASIS: REGULATION OF CELL PROLIFERATION/INFLAMMATION:

T cells play a central role in the pathogenesis of psoriasis, particularly Th17 cells. STAT3 promotes the differentiation of CD4+ T cells into Th17 and enhances the function of Th17 cells, thereby contributing to the development and progression of psoriasis [30,31]. The activation of STAT3 is associated with the proliferation and differentiation of Th17 cells, as well as the production and release of inflammatory cytokines such as IL-17. STAT3 binds to the promoters of genes such as IL-17A and IL-17F, which in turn promote the expression of genes such as IL-17, retinoic acid-related orphan receptor γt (RORγt), and aryl hydrocarbon receptor (AHR), inducing the differentiation and proliferation of Th17 cells and enhancing immune responses [32]. In addition, studies have shown that the activation of STAT3 can inhibit the function of regulatory Treg cells (T cells), preventing them from effectively suppressing inflammatory responses [33]. Moreover, studies have demonstrated that continuous activation of STAT3 can stabilize the characteristics of Th17 cells through epigenetic mechanisms (eg, histone modification), promote the formation of inflammatory memory, and accelerate the progression of psoriasis [34]. Therefore, by modulating the activity of STAT3, the function of Treg cells could be improved, which alleviates the symptoms of psoriasis (Figure 1).

In dendritic cells (DCs), activation of STAT3 significantly enhances their antigen-presenting ability and the secretion of pro-inflammatory factor IL-23 [35]. IL-23, by activating Th17 cells, forms a positive feedback loop, which continuously amplifies the inflammatory response and promotes the pathological process of psoriasis [36]. Single-cell sequencing studies have shown the association of the activation of STAT3 in DC subpopulations in psoriatic lesions with an increase in the secretion of CXCL chemokines, which further recruit neutrophils and Th17 cells to the affected skin area, continuously activating the inflammatory response [37] (Figure 2).

In the pathogenesis of psoriasis, STAT3 is a key signaling molecule that plays a central role by dynamically regulating the M1/M2 polarization state of macrophages [38]. Studies have demonstrated that the persistent abnormal activation of STAT3 drives macrophages to differentiate into pro-inflammatory M1 phenotype, which is accompanied by an increase in M1 markers such as CD86 and inducible nitric oxide synthase (iNOS), and promotes the release of inflammatory factors such as IL-6 and TNF-α [39]. This process forms a positive feedback loop with the NF-κB pathway, jointly exacerbating the local inflammatory response in the skin and the excessive proliferation of keratinocytes [40,41]. Thus, inhibiting the phosphorylation of STAT3 not only can downregulate the M1-related factors but also induce the transformation of macrophages to the anti-inflammatory M2 phenotype, which is manifested by the upregulation of M2 markers such as Arg-1 and IL-10, thereby partially restoring the immune regulatory function [42,43]. Notably, the regulation of macrophage polarization by STAT3 exhibits a biphasic pattern. A brief activation is therefore beneficial for the M2 phenotype and tissue repair, while sustained activation leads to the dominance of M1 polarization [44]. Recent studies have further disclosed that STAT3 is involved in the process of cellular metabolic reprogramming, such as by enhancing glycolysis to promote the inflammatory response of M1 macrophages [45–47]. Therefore, precisely targeting the JAK/STAT3/NF-κB signaling axis and regulating the threshold of STAT3 activity is expected to break the positive feedback loop of inflammation in psoriasis, thereby providing a new strategy for immune-metabolic reprogramming therapy (Figure 3).

In psoriasis, neutrophils act as the key inflammatory effector cells whose infiltration is directly regulated by the STAT3-signaling pathway. STAT3 has been shown to regulate the expression of neutrophil-attracting chemokines such as chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C-X-C motif) ligand 2 (CXCL2), and chemokine (C-X-C motif) ligand 8 (CXCL8), facilitating neutrophil infiltration into the skin [48,49]. Activated neutrophils release various proteases and reactive oxygen species (ROS), causing direct damage to keratinocytes and disrupting epidermal barrier integrity, thereby sustaining and exacerbating the local inflammatory microenvironment. STAT3 activation within neutrophils can induce the formation of neutrophil extracellular traps (NETs), which activate the Toll-like receptor 9 (TLR9)-signaling pathway and intensify the IL-17-mediated inflammatory response, forming an amplification loop of inflammation [50]. In summary, STAT3 regulates neutrophil chemotaxis, activation, and effector functions through multiple pathways and plays a central role in the inflammatory cascade of psoriasis (Figure 4).

In the pathogenesis of psoriasis, STAT3 induces the continuous amplification of inflammatory signals through a multi-level regulatory network. Upon activation by cytokines such as IL-17A, STAT3 induces keratinocytes to secrete a large amount of inflammatory mediators such as IL-6, IL-8, and CXCL1 [51]. These mediators recruit and activate immune cells such as neutrophils and sustain the activated state of STAT3 through a positive feedback mechanism [48,52]. Meanwhile, STAT3 synergizes with the NF-κB-signaling pathway to amplify the inflammatory cascade reaction [53]. Of note, the STAT3-mediated inflammatory microenvironment promotes Th17 cell differentiation and the secretion of cytokines such as IL-17, which in turn reactivates STAT3 in keratinocytes, thereby sustaining chronic inflammation [54,55].

Furthermore, STAT3 directly upregulates the expression of Cyclin D1, a cell cycle protein, thereby driving cell transition from the G1 phase to the S phase and accelerating the cell division cycle [56]. By increasing the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), STAT3 significantly enhances the resistance of keratinocytes to apoptosis [57,58]. Abnormally activated STAT3 also significantly inhibits the expression of key terminal differentiation markers such as filaggrin and involucrin, resulting in the abnormal structure of the keratin layer and impaired function of the skin barrier [59,60] It also triggers the abnormally high expression of proliferative keratins such as K16/K17, substituting normal differentiation-related keratins and further disrupting the normal structure and function of epidermal cells [61] (Figure 5).

STAT3 integrates signals from immune cells and stimulates keratinocytes to feedback and secrete factors such as IL-6, TNF-α, and sphingosine-1-phosphate (S1P) cytokines participate in immune activation and promote angiogenesis and neutrophil recruitment, thereby collectively sustaining chronic inflammation and epidermal hyperplasia [62].

Furthermore, STAT3 is involved in angiogenesis, inducing the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α, promoting abnormal dilation, curvature, and proliferation of capillaries in the dermal papillary layer, which clinically manifests as erythema in psoriasis [63,64].

TARGETED THERAPEUTIC STRATEGIES:

Given the pivotal role of STAT3 as a key signaling node in psoriasis pathogenesis, STAT3-targeted therapeutic strategies have been developed (Table 1).

SMALL-MOLECULE STAT3 INHIBITORS:

WB518 specifically inhibits IL-22– or IL-17A–induced STAT3Tyr705 phosphorylation in HaCaT cells, reducing mRNA and protein levels of the downstream target gene K17. Moreover, it exerts no significant effect on extracellular regulated protein kinase (ERK) or STAT1 pathways. In IMQ-induced mouse models of psoriasis, topical WB518 significantly reduced p-STAT3 levels in skin tissue, inhibited the expression of inflammatory factors IL-1β, IL-6, IL-17A, and IL-23, reduced the infiltration of CD3-positive T cells, and alleviated pathological symptoms such as epidermal hyperplasia, scales, and erythema [65].

The novel STAT3 inhibitor quinone derivative 15e promotes STAT3 ubiquitination and degradation, thereby downregulating the expression of the downstream target genes v-myelocytomatosis viral oncogene homolog (c-Myc) and Cyclin D1. In in vitro experiments, 15e exerted inhibitory activity at the nano-molar level on HaCaT cell proliferation, and its cytotoxicity was lower than that of the clinical drug anthralin. In IMQ-induced mouse models of psoriasis, topically applied 0.5% 15e gel significantly reduced STAT3 and p-STAT3 expression in the skin lesion tissue, and down-regulated plasma IL-17A and IL-17F levels. Histopathological examination revealed that 15e effectively reduces skin thickening, scaling, and inflammatory infiltration, and its efficacy was superior to that of 2% anthralin. Moreover, it exhibited no substantial toxicity to major organs such as the heart, liver, spleen, lungs, and kidneys, demonstrating good potential for clinical translation [66].

Lapatinib-derivative B20, an oxazolynoquinone compound, is a novel STAT3 inhibitor that directly binds to the STAT3 protein, thereby blocking its phosphorylation [67], dimerization, and nuclear translocation. In IMQ-induced mouse models of psoriasis, topical B20 effectively alleviated pathological features such as epidermal thickening, erythema, and scaling, and it lowered Psoriasis Area Severity Index (PASI) scores and decreased the secretion of pro-inflammatory factors (eg, IL-17A and IL-6) and Th17 cell infiltration. In vitro, B20 suppressed HaCaT cell proliferation and induced apoptosis by downregulating the expression of STAT3 target genes Cyclin D1 and Bcl-2 [68], and it exerted synergistic inhibitory effects on the cross-activation of JAK2/STAT3 and NF-κB pathways [69]. According to preclinical studies, B20 exhibits high selectivity and favorable local tolerability, although further pharmacokinetic evaluation and combination studies are needed to validate these findings [70,71].

GENE SILENCING AND EPIGENETICS:

Gene silencing technologies, such as RNA interference, which involves gene silencing, and regulatory approaches targeting epigenetic modifications, offer promising strategies for achieving precise and long-lasting modulation of pathogenic genes associated with psoriasis.

A novel anti-inflammatory lipid nanoparticle (LNP), C8B2, has demonstrated substantial efficacy in delivering Stat3 siRNA for psoriasis therapy. In vitro, C8B2 efficiently silences the Stat3 gene, markedly suppressing abnormal keratinocyte proliferation and promoting keratinocyte apoptosis. In animal models, locally applied C8B2-si-Stat3 significantly improves psoriasis-like symptoms. This treatment strategy exerts no obvious toxicity, indicating that this LNP delivery system, combining efficient gene silencing and its own anti-inflammatory function, is a new nucleic acid-based therapeutic approach for psoriasis [72].

The combination of STAT3 siRNA and ultrasound microbubble technology specifically knocks down STAT3 expression in keratinocytes, inducing apoptosis and inhibiting proliferation. The combined strategy is an innovative therapeutic approach for psoriasis in clinics [73].

Regarding epigenetic regulation, miR-4516 suppresses protein expression by binding to the 3′-UTR of STAT3, whereas miR-21-3p regulates the CDK4/6-EZH2-STAT3 axis, which is an important pathway integrating the regulation of cell proliferation, epigenetic modification, and inflammatory signaling, minimizing inflammation and proliferation [25].

INDIRECT TARGETING STRATEGIES FOR STAT3:

Tofacitinib, a JAK inhibitor, indirectly prevents STAT3 activation by inhibiting the phosphorylation of JAK kinases. It effectively modulates the key IL-23/IL-17 inflammatory axis and restores the Th17/Treg immune balance in psoriasis [74]. Clinical studies have confirmed that Tofacitinib has superior efficacy and safety compared to other JAK inhibitors such as Peficitinib and Baricitinib in psoriasis plaque treatment [75]; the 5 mg/10 mg BID dosage demonstrated a dose-dependent effect and markedly improved the PASI score at 16 weeks [76,77]. It is thus a crucial treatment option for moderate-to-severe plaque-type psoriasis.

Ustekinumab targets the p40 subunit common to IL-12 and IL-23, while gusizucabumab targets the more specific p19 subunit of IL-23 with greater precision [78,79]. By blocking IL-23, both of them effectively inhibit Th17 cell differentiation and function, thereby reducing the production of downstream inflammatory factors such as IL-17 and IL-22, and indirectly decreasing STAT3 activation [80]. In terms of clinical efficacy, both these drugs demonstrated a strong and sustained ability to clear skin lesions. The PASI 90 response rate for ustekinumab during long-term treatment was 43–62%, possibly due to its limitations of dual-target inhibition and lower affinity, whereas guselkumab exhibited superior ability to clear skin lesions (with a PASI 90 response rate of 76%) in head-to-head studies. Its high specificity, high affinity, and ability to achieve a more complete blockade of the IL-23 pathway improve the therapeutic effect [81].

Secukinumab and ixekizumab directly neutralize IL-17A, reducing p38 and STAT3 activities and thus alleviating the inflammatory response of keratinocytes and psoriasis severity, and they are currently first-line biologics [21,82]. In a prospective cohort study (n=65), both Secukinumab and Ixekizumab exhibited significant therapeutic efficacy against psoriasis lesions and nail disorders, and the therapeutic effects showed site specificity. At 24 weeks of treatment, 100% of patients in both the Secukinumab and Ixekizumab groups achieved a PASI 75 response, with excellent skin clearance rates. Both groups exhibited marked improvements in body surface area (BSA) and dermatology life quality index (DLQI) (BSA improvement rate >93%, DLQI improvement rate > 88%), with excellent safety and mild adverse events [83].

Recent studies have developed a long-acting recombinant IL-22 binding protein fused to an albumin-binding domain (IL-22BP-ABD) [84], efficiently produced using the Escherichia coli system. This fusion protein effectively prevents the binding of IL-22 to its receptor and inhibits STAT3 phosphorylation and the production of downstream inflammatory factors [22]. In the mouse psoriasis model induced by IMQ, it significantly improved skin symptoms, reduced the PASI score, alleviated pathological damage, and significantly inhibited the expression of key inflammatory factors, providing a new candidate drug for the treatment of psoriasis [85].

NATURAL COMPOUNDS AND HERBAL EXTRACTS:

Curcumin, a natural polyphenol, exhibits multi-target anti-inflammatory and antioxidant effects in psoriasis. Its key mechanisms include suppression of Th1/Th17-related cytokines (eg, IL-17 and TNF-α) and modulation of the JAK-STAT/Nrf2 pathway [86]. Preclinical studies have reported that curcumin-based formulations significantly reduce epidermal hyperplasia and improve skin barrier repair, with a favorable safety profile [87,88], but its clinical efficacy is limited by poor bioavailability. Randomized controlled trials (RCTs) indicated that combination therapies outperform curcumin monotherapy [89,90]. Novel drug delivery systems can enhance skin permeability and chemical stability. However, further large-scale clinical validation is warranted to clarify their therapeutic value [91,92]. Future work should focus on optimizing delivery strategies and evaluating synergistic effects with biologics to enhance the clinical translation of curcumin [93,94].

Piperine, another promising natural compound, regulates psoriasis-related pathways through multi-target regulatory mechanisms. In animal models, it inhibits STAT3 phosphorylation, thereby blocking Th17 cell differentiation and markedly downregulating the production of Th17-related cytokines such as IL-17A, IL-21, and IL-22 [70,95]. Piperine also suppresses NLRP3 inflammasome activation and IL-1β release, decreasing epidermal hyperplasia and inflammatory infiltration [95,96]. Ipiperine also suppresses nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and IL-1β release, decreasing epidermal hyperplasia and inflammatory infiltration [97]. Moreover, this drug enhances the bioavailability of other co-administered drugs by inhibiting CYP3A4 and P-glycoprotein. Novel delivery systems such as nano-liposomes can improve their transdermal penetration [98,99]. However, clinical evidence remains insufficient, and standardized formulations and phase I/II clinical trials are required to confirm its safety and determine optimal dosing [95,100]. Future studies should also investigate piperine’s multi-target synergistic effects when combined with biologics and explore its potential in managing psoriasis-related comorbidities [70,101,102].

Protocatechuic aldehyde, a tyrosine phosphorylation-specific STAT3 inhibitor, exerts multi-dimensional therapeutic effects in IMQ-induced mouse models of psoriasis by targeting and inhibiting STAT3 at the Y705 site [103]. It significantly down-regulates STAT3-dependent pro-inflammatory mediators and inhibits the release of cytokines such as IL-6 and TNF-α. This activity alleviates abnormal keratinocyte proliferation, reduces epidermal thickness by 46.2%, and restores skin barrier function [104]. By inhibiting hypoxia-driven inflammatory amplification through the STAT3-HIF-1α-NF-κB signaling cascade, protocatechuic aldehyde can synergistically regulate the IL-17/IL-23 axis to restore Th17 immune balance. By inhibiting hypoxia-driven inflammatory amplification through the STAT3-HIF-1α-NF-κB signaling cascade, protocatechuic aldehyde can synergistically regulate the IL-17/IL-23 axis to restore Th17 immune balance.

Future Directions

STAT3 is a core transcription factor regulating various cellular functions and plays a crucial role in the pathogenesis of inflammatory and autoimmune diseases such as psoriasis. Although therapeutic strategies targeting STAT3 have achieved considerable progress, its clinical application still encounters several challenges, and the precise regulatory mechanisms of this molecule within the skin immune microenvironment are not yet completely elucidated.

With respect to treatment strategies, current STAT3 inhibitors have 2 major limitations. First, insufficient target specificity can lead to systemic adverse effects such as immunosuppression [67,105]. Second, long-term medication can activate compensatory pathways, such as the feedback upregulation of the NF-κB and MAPK-signaling pathways, which can reduce therapeutic effectiveness [49,106]. To address these issues, emerging methods include increasing drug selectivity using tissue-specific delivery systems such as nanocarriers [107], developing multi-target inhibitors [108], or adopting a combined treatment strategy [109]. These methods are expected to improve the therapeutic effect while reducing systemic toxicity.

In the precision medicine field, biomarkers such as STAT3 phosphorylation levels and IL23R/JAK2 (the signaling unit composed of the IL-23 receptor and JAK2 kinase) polymorphisms are used to predict treatment responses, while the characteristics of the intercellular interaction between Th17 and keratinocytes revealed through single-cell sequencing help formulate individualized treatment plans [58,110,111]. In terms of mechanistic research, patient-derived skin organoid models can simulate the STAT3-mediated abnormal immune network, offering a platform for drug screening [103,112]. These studies have found that STAT3 regulates keratinocyte proliferation and immune cell inflammatory responses through various mechanisms, suggesting the need for tissue-specific regulatory tools [113]. Furthermore, emerging technologies, including ligand-targeted therapeutics and AI-optimized clustered regularly interspaced short palindromic repeats (CRISPR) systems, are believed to enhance treatment specificity and reduce off-target effects, further paving the way for refined individualized treatment plans [114].

The initiating factors and maintenance mechanisms for continuous STAT3 activation during psoriasis onset have not yet been defined in the skin immune network. Understanding factors that trigger abnormal STAT3 activation and form a positive feedback loop, thereby leading to aberrant proliferation and differentiation of keratinocytes and immune cells, is essential for defining strategies fundamentally blocking disease progression [14]. Furthermore, given the extensive physiological roles of STAT3 in various tissues, systemic inhibition can lead to unintended off-target effects [115]. Therefore, developing cell-type-specific targeting regulatory approaches is crucial for not only understanding the precise mechanism of STAT3 in psoriasis but also achieving safer interventions for clinical use. Future research should integrate multi-omics analyses with new drug delivery technologies to overcome current treatment bottlenecks and achieve safer and more durable clinical outcomes (Table 2).

Compared with recent reviews, the novelty of this article lies in its comprehensive integration of the multi-dimensional mechanism of STAT3 in psoriasis, covering not only the abnormal activation of classic immune cells (Th17, DC, macrophages, neutrophils) and keratinocytes, but also delving into emerging pathological links such as metabolic reprogramming, NETosis, and epigenetic regulation. The present review systematically summarizes the latest targeted treatment strategies from 2024 to 2025, including novel small-molecule STAT3 inhibitors (eg, WB518, 15e), gene silencing techniques (such as LNP-delivered siRNA), nano-delivery systems of natural compounds, and the efficacy comparison of clinical biologics, highlighting the cutting-edge directions of precise delivery, multi-target synergy, and individualized treatment.

Despite the promising progress in STAT3-targeted therapy for psoriasis, several critical challenges remain to be addressed for its clinical translation and optimization [116]. First, off-target effects remain a primary bottleneck: most current STAT3 inhibitors lack strict tissue and functional specificity, and non-specific inhibition of STAT3 in normal physiological tissues can disrupt basal immune homeostasis and cellular proliferation, leading to adverse reactions such as systemic immunosuppression, gastrointestinal disorders, and hematopoietic dysfunction [67,105]. Second, clinical trial evidence is insufficient: most novel STAT3-targeted candidates (eg, small-molecule inhibitors, gene silencing systems, natural compound derivatives) are still in preclinical or early phase I/II clinical trials, and there is a lack of large-sample, multi-center phase III clinical data to confirm their long-term efficacy and safety in psoriasis patients. Third, unelucidated mechanisms of crosstalk with other signaling pathways restrict the rational design of targeted therapies. The regulatory network of STAT3 with key psoriasis-associated pathways (eg, NF-κB, JAK/STAT family subtypes, PI3K/Akt) in the skin immune microenvironment has not been fully clarified, and the specific molecular mechanisms of compensatory pathway activation after STAT3 inhibition, which easily leads to therapeutic resistance, remain poorly understood. In addition, the unclear long-term safety of novel targeted strategies and the high research and development costs of precision delivery systems further limit their clinical popularization. Advancements in precision medicine (biomarkers, single-cell sequencing [58,110,111]) and mechanistic research (patient-derived organoids [103,112]) have informed individualized therapies, while emerging technologies (ligand-targeted therapeutics, AI-optimized CRISPR [114]) may reduce off-target effects. Additional challenges include unclear long-term safety and high treatment costs. Future research should prioritize phase III trials, optimize delivery systems, and clarify STAT3 mechanisms to maximize therapeutic potential and improve psoriasis patient outcomes.

Conclusions

Accumulating evidence has demonstrated that STAT3 is a core transcription factor essential for psoriasis pathogenesis, but its precise regulatory mechanisms in the skin immune microenvironment and clinical application of targeted therapies remain challenging. Current STAT3 inhibitors are limited by insufficient specificity (causing systemic off-target effects like immunosuppression and multi-organ disturbances [67,105]) and compensatory pathway activation reducing efficacy [49,106]. Emerging strategies (tissue-specific delivery, multi-target inhibitors, combination therapy [107]) show promise but lack phase III clinical trial validation for widespread use. This review systematically summarizes the role of STAT3 in psoriasis and the research progress of targeted therapies, providing a theoretical basis for the development of novel and effective antipsoriatic agents.