22 April 2026 : Review article
Role of the STAT3 Signaling Pathway in Cell Proliferation and Inflammation in Psoriasis and Approaches for Targeted Therapies: A Review
Limin Li CE 1, Lu Chen B 1, Cai Zhang BEF 2, Wenchao Yao D 1, Zhengxiao Li G 3, Faming Tian G 1,2*DOI: 10.12659/MSM.952449
Med Sci Monit 2026; 32:e952449
Table 1 Comparison of mechanisms, efficacy, and safety of STAT3-targeted therapies for psoriasis.
| Classify | Drug | Core mechanism of action | Safety profile | Therapeutic effect (animal model/in vitro experiment/clinical study) | References |
|---|---|---|---|---|---|
| Small-molecule inhibitors | WB518 | Specific inhibition of STAT3 Tyr705 phosphorylation induced by IL-22/IL-17A in HaCaT cells; downregulation of mRNA and protein expression of downstream target gene K17; no significant effects on ERK or STAT1 pathway | High target selectivity, no obvious toxic and adverse effects reported* | []65 | |
| Quinone derivative 15e | Promotes STAT3 ubiquitin degradation and down-regulates the expression of downstream target genes c-Myc and Cyclin D1 | Lower cytotoxicity than anthralin, no significant toxicity to major organs (heart, liver, spleen, lung, kidney) | In vitro studies: Exhibits nanomolar-level inhibition of HaCaT cell proliferation, with cytotoxicity lower than the clinically used anthralin.2. Animal model: 0.5% 15e gel reduced STAT3 and p-STAT3 expression in skin lesions, decreased plasma IL-17A and IL-17F levels, and improved skin thickening (superior efficacy to 2% anthralin) | []66 | |
| Laparin derivative B20 | Targeting the STAT3 SH2 domain to inhibit Tyr705 phosphorylation and dimerization; synergistic inhibition of NF-κB and activity | High target selectivity, good local tolerability | Animal experiments: reduce IL-17A, TNF-α, inhibit Th17 differentiation and epidermal hyperplasia; the efficacy is comparable to that of glucocorticoids, and the safety is better | [–]67 | |
| Natural compounds and herbal extracts | Curcumin | Inhibit Th1/Th17 cytokines (IL-17, TNF-α); regulate JAK-STAT/Nrf2 pathway; improve oxidative stress and skin barrier | Good safety profile, no obvious toxic and adverse effects reported* | Animal experiments: reduce epidermal hyperplasia, repair barrier; nano-gel preparation improves permeability. Clinical RCT displays that the combination therapy is better than the single drug, and the bioavailability of the single drug is low | [–]86 |
| Piperine | Inhibit STAT3 phosphorylation and Th17 differentiation; downregulate cytokines such as IL-17A and IL-21; inhibit NLRP3, inflammasome and NF-κB pathway | No obvious toxic and side effects reported, with dual effects of therapy and drug sensitization* | Animal model: relieve epidermal hyperplasia and inflammatory infiltration; enhance UVB phototherapy sensitivity; nano-lipidosome improve transdermal efficiency | [,–]70 | |
| Protocatechuic aldehyde | specific inhibition of STAT3-Y705 phosphorylation; regulation of STAT3-HIF-1α-NF-κB signaling cascade; inhibition of IL-6 and TNF-α release; regulation of IL-17/IL-23 axis | No obvious toxic and side effects reported, high specificity of target binding* | Animal model: reduced epidermal thickness by 46.2% and restored skin barrier function; down-regulated expression of IL-1α and CXCL9; inhibited abnormal proliferation of keratinocytes | [–]103 | |
| Indirect targeting strategies for STAT3 | |||||
| JAK inhibitor | Tofacitinib | Inhibition of JAK kinase phosphorylation indirectly blocks STAT3 activation; regulates IL-23/IL-17 inflammatory axis and Th17/Treg immune balance in psoriasis | Superior safety profile compared with other JAK inhibitors, low incidence of adverse reactions | Clinical studies demonstrate superior efficacy and safety compared to other JAK inhibitors such as pemetinib and baricitinib. The 5 mg/10 mg oral regimen, administered twice daily, shows dose-dependent effects with significant improvement in PASI scores after 16 weeks, particularly effective for moderate-to-severe plaque psoriasis | [–]74 |
| Cytokine inhibitorTargeting the IL-23/Th17 axis | Usilumab (IL-12/IL-23 inhibitor) | Targeting the p40 subunit shared by IL-12 and IL-23; blocking IL-23-mediated Th17 cell differentiation, indirectly inhibiting STAT3 activation | Mature clinical application, good safety profile with mild adverse reactions | Clinical study: Strong and lasting ability to clear lesions; long-term treatment PASI 90 response rate 43–62% | [–]78 |
| Guselkumab (IL-23 inhibitor) | Specific targeting of the p19 subunit of IL-23; blocking IL-23-mediated Th17 cell differentiation and indirectly inhibiting STAT3 activation. | High target specificity, no obvious severe adverse reactions, good safety profile* | Clinical study: Head-to-head study demonstrates superior lesion clearance efficacy to usilumab (76% PASI 90 response rate) | []81 | |
| Sucicizumab/Ixekizumab (IL-17A inhibitor) | sucicizumab/ezinavir (IL-17A inhibitor) | Excellent safety profile, mild adverse events with no severe reactions reported* | Clinical study (n=65): 100% of patients achieved PASI 75 response at 24 weeks; significant improvement in BSA (improvement rate >93%) and DLQI (improvement rate >88%); effective for nail lesions; adverse events were mild | [,–]21 | |
| * No obvious toxic or adverse effects reported: refers to the absence of treatment-related mortality, severe adverse events, or dose-limiting toxicity in published literature. STAT3 – signal transducer and activator of transcription 3; Tyr705 – tyrosine 705; IMQ – Imiquimod; Animal model – IMQ-induced psoriasis mice; K17 – keratin 17; ERK – extracellular signal-regulated kinase; STAT1 – signal transducer and activator of transcription 1; IL – interleukin; SH2 – Src homology 2 domain; TNF-α – tumor necrosis factor-alpha; Th17 – T helper 17 cell; Th17 – T helper 17 cell; UVB – ultraviolet B; Nrf2 – muclear factor erythroid 2-related factor 2; NLRP3 – NOD-LRR- and pyrin domain-containing protein 3; HIF-1α – hypoxia-inducible factor 1-alpha; NF-κB – nuclear factor kappa-B; CXCL9 – C-X-C motif chemokine ligand 9; JAK – Janus kinase; PASI – psoriasis area and severity index; BSA – body surface area; DLQI – dermatology life quality index; CDK4/6 – cyclin-dependent kinase 4/6; EZH2 – enhancer of zeste homolog 2; RCT – randomized controlled trial; siRNA – small interfering RNA; LNP – lipid nanoparticle; p-STAT3 – phosphorylated STAT3; CD3 – cluster of differentiation 3 positive T lymphocyte; c-Myc – cellular myelocytomatosis oncogene; BP – binding protein; ABD – albumin-binding domain; Treg – regulatory T cell; UTR – untranslated region. | |||||