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Signalingpathwaysandtargetedtherapiesforpsoriasis

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Signalingpathwaysandtargetedtherapiesforpsoriasis|

Psoriasis, a chronic inflammatory skin condition affecting millions globally, has long been a therapeutic challenge. While traditional treatments offered broad immunosuppression, the landscape has dramatically shifted with the advent of biologics and small molecules targeting specific **signaling pathways**. Understanding these intricate cellular communication routes is paramount for developing precise **targeted therapies for psoriasis**, offering patients unprecedented efficacy and safety. This article delves deep into the key immune pathways driving psoriatic inflammation, explores the revolutionary drugs designed to interrupt them, and examines the future of personalized treatment strategies. ? The move from broad suppression to pinpoint accuracy marks a significant leap forward in managing this complex disease.

The IL-23/Th17 axis stands as the central conductor orchestrating psoriatic inflammation. ? This crucial **signaling pathway** begins when antigen-presenting cells release interleukin-23 (IL-23). IL-23 then binds to receptors on naive T-cells, prompting their differentiation into pro-inflammatory T-helper 17 (Th17) cells. These Th17 cells subsequently produce effector cytokines like IL-17A, IL-17F, and IL-22. These molecules act on keratinocytes (skin cells), triggering hyperproliferation, abnormal differentiation, and the recruitment of more inflammatory cells, creating the characteristic red, scaly plaques. Drugs like ustekinumab (targeting the shared p40 subunit of IL-12/IL-23), guselkumab, risankizumab, and tildrakizumab (specifically targeting IL-23p19), and secukinumab, ixekizumab, and brodalumab (targeting IL-17A or its receptor) represent the most effective class of **targeted therapies for psoriasis**, achieving PASI 90 (90% skin clearance) in a majority of patients within weeks.

While the IL-23/Th17 pathway dominates current research and treatment, the Tumor Necrosis Factor-alpha (TNF-α) pathway was the pioneering target for biologic **therapies for psoriasis**. TNF-α, produced by macrophages, T-cells, and mast cells, is a potent pro-inflammatory cytokine. It activates endothelial cells (promoting immune cell infiltration), stimulates keratinocyte proliferation, and induces the production of other inflammatory mediators like IL-8 and adhesion molecules. ? Early biologics like infliximab, adalimumab, and etanercept revolutionized treatment by directly neutralizing TNF-α or its receptor. These agents demonstrated significant efficacy, proving that targeting specific immune mediators was a viable strategy, paving the way for the development of drugs against IL-23 and IL-17. While less dominant than IL-23/Th17 inhibitors today, TNF blockers remain crucial options, especially for patients with concomitant psoriatic arthritis.

Beyond cytokine-specific biologics, targeting intracellular **signaling pathways** offers another powerful approach via small molecule inhibitors. The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a critical signaling hub downstream of numerous cytokine receptors, including those for IL-23 and IL-22. When cytokines bind their receptors, JAK enzymes phosphorylate, activating STAT proteins which then translocate to the nucleus to regulate gene expression involved in inflammation and proliferation. ? Oral JAK inhibitors like tofacitinib and upadacitinib work by blocking JAK enzymes, thereby dampening the signal from multiple pro-inflammatory cytokines simultaneously. Deucravacitinib represents a novel twist, selectively inhibiting TYK2, a JAK family member crucial for IL-23 and Type I interferon receptor signaling, offering high efficacy with a potentially favorable safety profile. These small molecules provide convenient oral alternatives to injections.

The success of existing **targeted therapies** fuels intense research into novel **signaling pathways** and emerging targets. The IL-36 pathway, part of the IL-1 cytokine family, shows significant promise. IL-36 cytokines (IL-36α, β, γ) are highly expressed in psoriatic skin and drive keratinocyte activation and neutrophil recruitment. Spesolimab, an anti-IL-36 receptor antibody, has shown remarkable efficacy in treating generalized pustular psoriasis (GPP), a rare and severe form. ? Other investigational approaches include targeting the aryl hydrocarbon receptor (AhR) involved in skin barrier regulation, phosphodiesterase 4 (PDE4) to modulate intracellular cAMP (with apremilast being an approved oral PDE4 inhibitor), and components of the NF-κB pathway, a master regulator of inflammation. The goal remains identifying targets offering optimal efficacy with minimal long-term safety concerns.

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相关配图

The future of **targeted therapies for psoriasis** lies in personalization and combination strategies. ? As our understanding of disease heterogeneity deepens, identifying biomarkers predictive of response to specific **signaling pathway** inhibitors will be key. Genetic profiling, cytokine signatures, and clinical phenotypes may guide clinicians towards the most effective first-line biologic or small molecule for an individual patient. Furthermore, combining agents targeting different pathways (e.g., an IL-23 inhibitor with a TYK2 inhibitor) holds potential for patients with difficult-to-treat disease or inadequate response to monotherapy, though safety data for such combinations are still evolving. Ongoing research focuses on achieving sustained remission or even a cure, exploring strategies like immune tolerance induction.

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In conclusion, deciphering the complex immune **signaling pathways** underlying psoriasis has been transformative. The development of highly specific **targeted therapies**, particularly biologics blocking IL-23 and IL-17, and small molecules inhibiting JAK-STAT signaling, has revolutionized patient care, offering unprecedented levels of skin clearance and improved quality of life. ? While current treatments are highly effective for many, ongoing research into novel pathways like IL-36 and strategies for personalization and combination therapy promises even more refined and powerful solutions for all individuals living with psoriasis in the years to come. The era of targeted intervention is firmly established and continuously evolving.

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  • 来源: 抖音新闻
    作者: 高博、赵佑

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