Targeting the PSMB9–NGAL/MMP9 Axis: a novel neutrophil-driven mechanism and precision target for vascular remodeling in PAH

Background Achieving transformative outcomes in pulmonary arterial hypertension (PAH) requires a precise understanding of the mechanisms sustaining TGF-β activation and vascular remodeling. While the TGF-β pathway is central to PAH pathogenesis, the specific drivers that trigger its latent form remain a critical knowledge gap. We previously identified a lesion-specific neutrophil subset characterized by aberrant immunoproteasome PSMB9 activation and an NGAL/MMP9 proteolytic signature. However, the causal role of this PSMB9-driven axis in sustaining remodeling signals remains to be defined. Objective To establish the causal role of neutrophil PSMB9-driven NGAL/MMP9 proteolysis in TGF-β activation, Smad2/3 signalling and remodelling, and to define NF-κB/ZEB1-dependent control of NGAL/MMP9. Methods A translational multi-omic approach was employed using human PAH lung tissues and plasma to quantify and map the NGAL/MMP9 axis across disease stages. To establish causality, we utilized neutrophil-specific conditional deletions of Psmb9,Ngal, and Mmp9 in experimental pulmonary hypertension (PH) models. Advanced in situ assays and co-culture systems quantified proteolysis-linked TGF-β activation, Smad2/3 signaling, and pulmonary artery smooth muscle cell (PASMC) proliferation. The robustness of this axis was further validated through genetic and pharmacological perturbations across multiple PAH phenotypes. Results Clinical Relevance NGAL/MMP9 levels and MMP9 activity were significantly elevated in human PAH lesions, tracking closely with disease severity and hemodynamic impairment. Causal Mechanism Neutrophil-specific Psmb9 deletion suppressed the NF-k/ZEB1-dependent NGAL/MMP9 output, leading to a marked reduction in active TGF-β activation, and downstream Smad2/3 signaling. Therapeutic Impact Disruption of this axis—either genetically or pharmacologically—reduced PASMC proliferation, improved pulmonary hemodynamics, and reversed vascular remodeling across diverse PH models. Translational Value The PSMB9–NGAL/MMP9 signature serves as a reproducible indicator of pathogenic remodeling across clinical PAH subtypes. Conclusion This study identifies PSMB9 as a master regulator that couples neutrophil proteolysis to TGF-β activation, driving the vascular remodeling hallmark of PAH. This newly defined PSMB9–NGAL/MMP9–TGF-β–Smad2/3 axis represents a high-value therapeutic target. Furthermore, its role as a robust biomarker aligns with the ESC 2026 focus on precision medicine and digital transformation, providing a molecular framework for AI-integrated risk stratification and personalized treatment strategies in cardiovascular care.