Targeting JAK–STAT signaling for autoimmune diseases: current understanding, clinical advances, and emerging directions

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling cascade for the survival, activation, maturation, and differentiation of immune cells through interactions with cytokine receptors and transcription factors. Growing evidence indicates that autoimmune disorders are markedly affected by the JAK-STAT axis. Understanding the architecture and functions of the JAK-STAT axis has spurred the creation and authorization of a number of medications for managing autoimmune conditions in clinical settings. A mass of therapeutic agents (e.g., JAKinibs tofacitinib, baricitinib, STATinibs Stattic, FLLL32) and non-coding RNA have been used in research in preclinical experiments or/and clinical trials and demonstrate significant potential for treating autoimmune diseases. Nevertheless, concerns about these medicines' long-term safety and possible adverse consequences still exist. This narrative overview elaborates on the exact molecular underpinnings of the JAK-STAT axis, while also exploring the links among this pathway, adaptive immune cells, and autoimmune disorders. We also summarize the recently developed inhibitors of this pathway along with the present issues and future directions in the field.