Kaur, P.; Jankowski, K.; Ghosh, A.; Santos-Gallego, C. G.; Ambade, A.; Duran, T.; Zibaoui, Y. E.; Ochoa, M. T.; Mansoori, M.; Poor, H.; Sassi, Y.; Hassoun, P. M.; Bisserier, M.; Hadri, L.

Background. Interleukin-6 (IL-6) is a central driver of pulmonary vascular remodeling in idiopathic, heritable, and connective tissue disease-associated pulmonary arterial hypertension (PAH). Elevated IL-6 correlates with right ventricular (RV) dysfunction and poor survival. However, the specific downstream mechanisms by which IL-6 drives pathogenesis remain poorly defined. We investigated the therapeutic impact of direct IL-6 neutralization and its regulation of a novel epigenetic signaling axis in PAH. Materials and Methods. We evaluated species-specific IL-6-neutralizing antibodies in murine Sugen/hypoxia and rat monocrotaline models of PAH. RV structure and function were assessed using cardiac MRI and invasive hemodynamics. Lung transcriptomic profiling was performed by RNA sequencing mouse lung tissue. Key findings were validated in explanted human PAH lungs, serum, and peripheral blood mononuclear cells (PBMCs), and further interrogated through mechanistic in vitro studies in human pulmonary artery endothelial cells (PAECs). Results. IL 6 neutralization significantly improved RV function, reduced pulmonary arterial pressures, and attenuated pulmonary vascular remodeling in both experimental models. Transcriptomic analysis identified a dysregulated FOXP3 signaling axis. Mechanistically, IL 6 induced cooperative binding of phosphorylated STAT3 and STAT4 to the FOXP3 promoter, facilitating DNMT1 mediated DNA methylation and stable gene silencing. IL 6 blockade restored downstream FOXP3 expression, rescued downstream BMPR2 signaling, and re established endothelial homeostasis. In clinical PAH cohorts, FOXP3 expression was markedly reduced and inversely correlated with circulating IL-6 levels and indices of disease severity. Conclusion. IL 6 drives pulmonary hypertension through STAT3/STAT4 and DNMT1 dependent epigenetic repression of FOXP3, linking chronic inflammation to BMPR2 dysfunction and pulmonary vascular remodeling. IL 6 neutralization reverses this pathogenic program in experimental PAH. FOXP3 emerges as a mechanistic biomarker of disease severity and a potential tool for precision stratification of patients likely to benefit from IL 6-targeted therapies.