JAK-STAT pathway-associated skin diseases: a refined functional framework for inflammatory skin diseases

Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in the pathogenesis of a variety of inflammatory and autoimmune skin diseases, such as atopic dermatitis (AD), psoriasis, alopecia areata (AA), vitiligo, etc. Many cytokines are involved in the occurrence and development of these diseases through the JAK-STAT-mediated intracellular signaling. Small molecule JAK inhibitors (JAKi) have demonstrated substantial efficacy in the treatment of many diseases, especially in inflammatory skin diseases. For example, abrocitinib and upadacitinib have been approved for the treatment of moderate-to-severe AD, and baricitinib has been approved for the treatment of severe AA. Meanwhile, clinical and preclinical studies of various JAKis for other skin diseases are ongoing. However, the traditional classification of inflammatory skin diseases according to the T helper (Th) immune axis fails to distinguish between cytokine signals that are mechanistically dependent on the JAK-STAT pathway and those that are not, thus limiting its utility for guiding targeted therapy. Accordingly, we propose a functional refinement framework that integrates JAK-dependent cytokine modules into the established Th immune axis system. This article reviews the pathogenesis of "JAK-STAT pathway-associated skin diseases" and the available efficacy evidence of JAKi therapy, aiming to improve the mechanistic understanding and rational clinical application of JAKi and provide valuable references for clinical diagnosis and treatment.

Keywords: JAK inhibitors; JAK-STAT signaling pathway; autoimmune disease; cytokines; helper T cells; inflammatory skin diseases.