An exhaustive examination of the research progress in identifying potential JAK inhibitors from natural products: a comprehensive overview.

Abstract

The JAK-STAT signaling pathway serves as a central regulator of diverse cellular processes encompassing proliferation, apoptosis, inflammation, and differentiation. Specifically, extracellular ligands such as interleukins, and colony-stimulating factors induce JAKs phosphorylation, subsequently triggering dimerization and nuclear translocation of STATs protein. In this way, the JAK-STAT pathway modulates target gene expression. Dysregulation of the JAK-STAT pathways has been implicated in the pathogenesis of multiple diseases, including inflammatory diseases, autoimmune diseases, malignant tumors. Therefore, JAK inhibitors have been considered promising therapeutic candidates with substantial clinical potential. While previous reviews have primarily focused on natural products targeting JAK-STAT signaling pathways for the specific disease application, this paper comprehensively collected 88 natural products demonstrating JAKs inhibitory activity across multiple pathological conditions. We mainly referenced nearly 20 years of literature from 2005 to 2025, comprising 294 different types of publications including review articles and research papers. Through systematic analysis of the compounds, we further classified these phytochemicals according to their structural characteristics (flavonoids, alkaloids, terpenoids) and molecular targets within the signaling cascades. This study provides novel insights into the pathophysiological relationships between diseases and JAK kinases, while offering valuable guidance for developing next-generation JAK inhibitors with improved therapeutic profiles.