JAK-STAT Signaling: Mechanisms and Therapeutics in Stem Cell Biology

The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway is a conserved signaling system that links extracellular cytokine signals to transcriptional regulation of genes controlling cell proliferation, differentiation, and survival. Increasing evidence demonstrates that this pathway plays central roles in stem cell biology across diverse systems, including pluripotent stem cells, adult tissue stem cells, and cancer stem cells. In pluripotent stem cells, STAT3 signaling downstream of leukemia inhibitory factor (LIF) supports self-renewal and maintenance of the undifferentiated state, whereas in adult stem cells, JAK-STAT activity regulates the balance between quiescence, proliferation, and lineage commitment. Stem cell niches further modulate pathway activity through spatially and temporally controlled cytokine signals that coordinate regenerative responses with tissue homeostasis. Recent studies have also revealed noncanonical functions of STAT proteins, including mitochondrial STAT3-dependent metabolic regulation and unphosphorylated STAT-mediated chromatin and heterochromatin regulation that influence stem cell identity and function. Dysregulation of the pathway contributes to pathological conditions, including inflammatory disorders and cancers characterized by stem-like cell populations. Therapeutic targeting of JAK-STAT signaling therefore represents an important strategy in both regenerative medicine and oncology. This review summarizes recent advances in understanding how JAK-STAT signaling regulates stem cell biology, highlighting emerging mechanisms of pathway integration, niche regulation, and therapeutic modulation.