The JAK/STAT pathway: a pivotal therapeutic target in disease and advances in natural product modulation

The JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway was discovered during the investigations on cellular responses to interferons (IFNs) in the early 1990s, and its components and functions were gradually elucidated and refined in the subsequent years. Serving as a core mediator of extracellular signal transduction such as cytokines and growth factors, the JAK/STAT signaling pathway plays a pivotal role in various diseases, representing an attractive therapeutic target. Although synthetic agents targeting this pathway have demonstrated clinical efficacy, long-term administration is frequently associated with adverse effects such as immunosuppression and infection risks. In recent years, natural products have emerged as novel candidates for modulating JAK/STAT signaling pathway, owing to their structural diversity, multi-target mechanisms and low-toxicity profiles. This review offers a comprehensive elucidation of the JAK/STAT signaling pathway, covering its discovery history, core components and transmembrane signal transduction mechanisms, and underscores its essential functions in the progression of diverse diseases. Furthermore, this review focuses on summarizing the research progress on natural products that modulate the JAK/STAT pathway from 2021 to 2025, and traces the research history of related natural products. This review aims to comprehensively demonstrate the development potential of natural products as drug lead compounds targeting the JAK/STAT pathway, thereby providing a theoretical foundation for subsequent studies.