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The JAK/STAT signaling pathway functions as a bridge between intracellular and extracellular signaling processes. The pathway includes three main parts: The JAK/STAT pathway includes tyrosine kinase-related receptors (RTKs), Janus kinases (JAKs), and signal transducers and activators of transcription (STATs) as its main components. The JAK-STAT signaling pathway features a transmission process that remains simpler than other signaling pathways. The signal transmission process is as follows: Cytokine binding to receptors leads to receptor dimerization which brings JAK kinases together to activate through mutual tyrosine phosphorylation. Following JAK activation the kinase induces phosphorylation of tyrosine residues on the receptor which then create "docking sites" for surrounding protein sequences and attract STAT proteins with SH2 domains to these sites. The kinase JAK performs phosphorylation on the STAT protein attached to the receptor which enables the activated STAT protein to move into the cell nucleus as a dimer and bind to target genes to control transcription. One JAK kinase participates in multiple cytokine signaling processes while multiple JAK kinases can be activated by a single cytokine signaling pathway although cytokines selectively activate specific STAT molecules. IL-4 triggers STAT6 activation whereas IL-12 induces STAT4 activation. Diseases like cancer and autoimmune diseases develop with the participation of the JAK/STAT signaling pathway which plays critical roles in their progression. Research into drug development for this pathway has intensified because inhibitors of JAK proteins now treat multiple diseases.
Figure 1. Schematic representation of mechanism of action and selectivity of JAK and TYK2 inhibitors. (Sources: Dragotto M, et al. 2024)
Psoriasis manifests as a chronic skin disease yielding inflamed skin with red lesions and increased thickness and scaling. The condition presents itself with red patches covered by silvery-white scales that appear most often on the scalp before spreading to both elbows, knees and lower back areas. Psoriasis develops through immune system malfunction which activates T cells excessively and results in abnormal skin cell growth alongside enlarged blood vessels and inflammatory cell infiltration.
Genetic inheritance together with environmental factors cause Psoriasis development. HLA-B13, B17, and Cw6 genes serve as genetic factors for psoriasis whereas environmental triggers include infection and trauma as well as stress and particular medications. Multiple systemic conditions such as cardiovascular disease and metabolic syndrome alongside arthritis are connected to psoriasis according to scientific research.
The five main clinical presentations of psoriasis are vulgaris which stands as the predominant form along with pustular, arthritic, erythrodermic, and palmoplantar types. Psoriasis vulgaris commonly shows up as mirror-image red patches covered with silvery scales spread over extensive body areas.
Studies show that the JAK/STAT signaling pathway maintains a robust link to psoriasis development. The activation of the JAK/STAT signaling pathway occurs through multiple cytokines and growth factors which then regulate gene expression responsible for cell proliferation differentiation and inflammatory responses. The cytokines associated with psoriasis such as IL-23, IL-17, IL-22 and IFN-γ activate the JAK/STAT signaling pathway. IL-23 binds to the JAK/STAT signaling pathway receptor to trigger the activation of JAK1, JAK2, and TYK2 which leads to STAT3 phosphorylation and nuclear translocation causing production of inflammatory factors IL-17, IL-21, and IL-22 essential for psoriasis development. Inflammation and immune cell activation become stronger through IFN-γ mediated activation of JAK1/2 dimers and STAT1.
JAK inhibitors prevent psoriasis inflammation by blocking JAK1/3 and TYK2 and disrupting IL-23/IL-17 and IL-22/Th22 pathways which reduces inflammatory factor production and release. Doctors who prescribe JAK inhibitors need to be careful because these drugs carry risks of increased infection chances along with blood toxicity.
The JAK/STAT signaling pathway supports psoriasis progression through regulation of different cytokines and inflammatory factors. Employing JAK inhibitors to target the JAK/STAT signaling pathway presents a new therapeutic strategy for treating psoriasis.
| Drug Name | Mechanism of Action | Indications | Efficacy Data | Limitations/Status |
| Tofacitinib | A pan-JAK inhibitor that mainly inhibits JAK1/3 and also acts on JAK2/TYK2. | Approved for psoriatic arthritis (PsA). | - Phase III trial: The PASI 75 response rate in the 10 mg twice - daily group was 59.1%, better than the placebo (10%). - In Japanese patients, the PASI 75 in the 10 mg group reached 75%, and the efficacy lasted for 52 weeks. | The FDA has not approved it for plaque psoriasis due to cardiovascular and infection risks. |
| Upadacitinib | A selective JAK1 inhibitor with better safety than the first - generation. | Adult patients with active PsA. | - SELECT - PsA trial: The efficacy is better than adalimumab, with continuous remission at 56 weeks. - Phase II study: The PASI 75 response rate in the 8 mg group was 42.9%, and it reached 54.1% in the 10 mg group. | |
| Deucravacitinib | A highly selective allosteric TYK2 inhibitor that blocks the IL - 23/IL - 12 signaling pathway. | The world's first TYK2 inhibitor approved for moderate - to - severe plaque psoriasis. | Phase III trial: The PASI 75 response rate in the 6 mg daily group was significantly higher than the placebo, with good long - term safety. | |
| Baricitinib | A JAK1/2 inhibitor that inhibits IFN - γ and IL - 6 signaling. | Phase II trial: The PASI 75 response rate in the 8 mg group was 42.9%, maintained for 24 weeks. | Not approved for psoriasis indications yet, mainly used for rheumatoid arthritis. | |
| Abrocitinib | Relieves inflammation through JAK1 inhibition for atopic dermatitis. | It showed effectiveness against psoriasis - related pruritus in clinical trials, but the data is limited. |
The JAK/STAT signaling pathway operates as an essential cellular communication mechanism. Receptors on cell surfaces trigger this process when cytokines and growth factors outside the cell attach to them. The signaling pathway consists mainly of tyrosine kinase-related receptors (RTK), Janus kinases (JAKs), and signal transducers and activators of transcription (STATs). When a receptor activates JAK kinase acts to phosphorylate the receptor first then moves to phosphorylate the STAT protein. The STAT protein forms a dimer and moves into the cell nucleus where it controls gene transcription expression. The regulation affects multiple biological functions that involve cell growth and differentiation together with programmed cell death and immune system responses.
Psoriasis represents a skin condition which persists by developing ongoing inflammatory episodes throughout its entire course. Distinct red patches that feature silvery-white scales and thickened skin characterize psoriasis which typically develops on the scalp and extends to the elbows knees and lower back. The disease starts when T cells in the immune system become overly active which initially results in keratinocyte overgrowth before causing blood vessel expansion accompanied by inflammatory cell buildup. The disease manifests from both genetic elements like HLA - B13, B17, and Cw6 genes as well as environmental factors including infections, trauma and drug use along with stress. People who suffer from psoriasis face heightened chances of developing systemic illnesses including cardiovascular disease along with metabolic syndrome and arthritis.
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