The JAK/STAT conundrum with mutational heterogeneity, immune defects, and the emergence of targeted therapies.

Introduction: The Janus kinase/signal transducer and activator of transcription signaling pathway orchestrates crucial aspects of immune regulation, including cytokine signaling, cellular proliferation, differentiation, and apoptosis. Dysregulation of this pathway due to gain- or loss-of-function mutations significantly contributes to the development of inborn errors of immunity and various immune-mediated disorders. Understanding the molecular basis of these abnormalities is fundamental for enhancing diagnostic precision and developing targeted therapies.

Areas Covered: A bibliographic search was conducted in PubMed and MEDLINE for articles published up to June 2025. The review offers a comprehensive overview of the structural and functional features of JAK/STAT family proteins, the intrinsic regulatory mechanisms, and the immunopathological consequences of STAT1, STAT3, and STAT6 gain-of-function diseases. Recent clinical advances, particularly the therapeutic impact of JAK inhibitors (JAKinibs) and emerging novel molecules, are critically discussed, emphasizing the integration of molecular insights into clinical practice.

Expert Opinion: Advances in the molecular characterization of JAK/STAT pathway dysregulation have opened new avenues for precision medicine approaches. While JAKinibs have shown promising outcomes, further research is needed to optimize therapeutic strategies, identify predictive biomarkers, and refine patient selection to maximize clinical benefits. Novel targeted therapies can reshape the management of JAK/STAT-related diseases in the coming years.