The JAK/STAT pathway: key mechanism in gene activation, disease regulation, and emerging therapeutic targets

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a fundamental intracellular mechanism that mediates cytokine and growth factor signaling. Dysregulation of this pathway through genetic mutations, polymorphisms, or persistent activation has been strongly associated with autoimmune diseases, inflammatory disorders, and a wide range of hematologic and solid malignancies. Consequently, the JAK/STAT pathway has emerged as a major therapeutic and diagnostic target in precision medicine. This review synthesizes evidence from experimental, translational, and clinical studies addressing the molecular structure, activation mechanisms, and regulatory control of JAK and STAT proteins. Aberrant JAK/STAT signaling contributes significantly to the pathogenesis of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as malignancies including myeloproliferative neoplasms, lymphomas, and breast cancer. Somatic mutations, transcriptional activation signatures, and phosphorylated STAT proteins serve as valuable diagnostic and prognostic biomarkers. JAK inhibitors, including ruxolitinib and tofacitinib, demonstrate clinical efficacy; however, treatment resistance, adverse effects, and incomplete disease modification remain significant challenges. The involvement of JAK/STAT signaling in metabolic, cardiovascular, and neuroinflammatory diseases remains insufficiently explored. Predictive biomarkers for patient stratification and long-term treatment outcomes are not yet fully established.

This review is limited by reliance on heterogeneous published data and the scarcity of long-term clinical trials validating biomarker utility and resistance mechanisms. This review uniquely integrates the molecular structure, regulatory mechanisms, diagnostic biomarkers, therapeutic targeting, and resistance mechanisms of the JAK/STAT pathway across autoimmune diseases and malignancies.

The JAK/STAT pathway is a central regulator of immune and inflammatory signaling with broad clinical relevance. The continued integration of molecular diagnostics, novel STAT-targeted agents, and combination therapies is essential for improving therapeutic precision and clinical outcomes.