Janus kinase and Signal Transducer and Activator of Transcription pathway (JAK-STAT pathway)

The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway is a critical intracellular signaling mechanism that mediates cellular responses to a wide array of cytokines, interferons, and growth factors [1, 14]. This evolutionarily conserved pathway provides a direct and rapid communication channel from cell-surface receptors to the nucleus, where it regulates essential biological processes including hematopoiesis, immune cell development, and cell survival [6, 14]. The pathway typically involves the activation of receptor-associated JAKs (JAK1, JAK2, JAK3, or TYK2), which then phosphorylate STAT proteins (STAT1-4, 5A, 5B, or 6), leading to their dimerization and nuclear translocation to drive gene transcription [10, 12]. Dysregulation or constitutive activation of JAK-STAT signaling is a fundamental driver in the pathogenesis of various autoimmune diseases, inflammatory conditions, and hematologic malignancies [2, 4, 13]. Consequently, the pathway has become a major therapeutic focus, specifically through the development of small-molecule JAK inhibitors (jakinibs) that block kinase activity to suppress pathological inflammatory and oncogenic signaling [3, 5, 8]. While these drugs have revolutionized the treatment of conditions like rheumatoid arthritis and myelofibrosis, their use is associated with safety concerns such as increased infection risk and hematological abnormalities due to the pathway's broad physiological roles [3].

Other names

JAK-STAT signaling pathwayJAK/STAT pathwayJanus kinase/signal transducer and activator of transcription signaling pathway

Inhibition of Janus kinases (JAKs) to prevent the phosphorylation and subsequent dimerization of Signal Transducer and Activator of Transcription (STAT) proteins, thereby blocking their translocation to the nucleus and preventing the transcription of cytokine-responsive genes.