Signal transducer and activator of transcription 3 (STAT3) and bone morphogenetic protein type 2 receptor (BMPR2) signaling axis (STAT3–BMPR2 signaling)

The STAT3–BMPR2 signaling axis refers to the interaction between the cytokine-activated transcription factor STAT3 and the bone morphogenetic protein type 2 receptor (BMPR2), which together play a critical role in pulmonary arterial hypertension (PAH). STAT3 is activated by cytokines such as IL-6 and growth factors, leading to its phosphorylation and nuclear translocation, where it regulates genes involved in cell proliferation, survival, and vascular remodeling[2]. In PAH, STAT3 hyperactivation represses BMPR2 expression, partly through upregulation of the miR-17/92 cluster, which targets BMPR2 mRNA[1][2]. Reduced BMPR2 signaling disrupts SMAD-dependent pathways, promoting pulmonary vascular cell proliferation and resistance to apoptosis—hallmarks of PAH[1][4]. Restoring BMPR2 expression, either directly or by inhibiting STAT3 (e.g., with HJC0152), can reverse these effects. The calcium-handling protein SERCA2a also regulates this axis by inhibiting STAT3, thereby upregulating BMPR2 and downstream SMAD signaling, and attenuating vascular remodeling[1]. Thus, the STAT3–BMPR2 axis represents a therapeutic target in PAH, with interventions aiming to restore BMPR2 signaling and inhibit pathologic STAT3 activation to prevent disease progression[1][2].

Other names

STAT3–BMPR2 pathwaySTAT3/BMPR2 interactionSTAT3–BMPR2–SMAD axis

STAT3 inhibition reduces pulmonary vascular cell proliferation and restores BMPR2 expression; SERCA2a overexpression inhibits STAT3 activity and enhances BMPR2–SMAD signaling; combination gene therapy and small-molecule STAT3 inhibitors attenuate pulmonary vascular remodeling and improve right ventricular function in PAH models[1]