A new PDGFRβ inhibitor ameliorates pulmonary hypertension via improving metabolic functions with reduced inflammatory environments

Pulmonary arterial hypertension (PAH) remains a life-threatening disease driven by pulmonary vascular remodeling, in which the metabolic switch to aerobic glycolysis (Warburg effect) in pulmonary arterial smooth muscle cells (PA-SMCs) plays a critical yet therapeutically unaddressed role. Existing platelet-derived growth factor receptor (PDGFR) inhibitors like imatinib show efficacy but have severe side effects and fail to correct the aerobic glycolytic reprogramming. Here, we developed a novel evodiamine-derived compound, ZL002 , which potently targets PDGFR β and inhibits downstream JAK2/STAT3 and HIF-1 α signaling. Unlike conventional PDGFR inhibitors, ZL002 restores the Warburg effect in PA-SMCs by Seahorse analysis and HIF-1 α nuclear translocation suppression. This metabolic correction is accompanied by restoration of mitochondrial dynamics, reduction of oxidative stress, and attenuation of M1 macrophage polarization. In multiple preclinical PAH models (hypoxia-induced mice, MCT-induced rats, and SuHx-induced mice/rats), ZL002 showed equivalence efficacy to sildenafil, imatinib and ruxolitinib, with improved pulmonary hemodynamics, reversed vascular remodeling, and no observed toxicity. ZL002 exhibits high oral bioavailability (76.2%) and a favorable safety profile (LD 50 > 2000 mg/kg). By demonstrating that a PDGFR inhibitor can actively correct the aerobic glycolytic switch, this study establishes a new signaling-metabolism dual-targeting paradigm for PAH therapy and positions ZL002 as a promising clinical candidate.