FABP4 Inhibitor Improves Right Ventricular Fibrosis in Metabolic Syndrome‐ Related Pulmonary Hypertension due to Left Heart Disease in Mice

ABSTRACT Pulmonary hypertension due to left heart disease (PH‐LHD) is a prevalent and fatal condition with limited therapeutic options. This study investigates the role and mechanisms of fatty acid binding protein 4 (FABP4) in PH‐LHD development. Plasma FABP4 levels were significantly elevated in PH‐LHD patients ( n = 36) compared to left heart disease patients without PH (noPH‐LHD, n = 33) and correlated positively with NT‐proBNP. Microarray analysis of GSE236251 identified differentially expressed genes in PH‐LHD, with KEGG enrichment highlighting relevant pathways. A PH‐LHD mouse model was established using metabolic syndrome (MetS) combined with pressure overload, revealing increased FABP4 expression in plasma, heart, and adipose tissue. Treatment with the FABP4 inhibitor BMS309403 (BMS) significantly reduced MetS‐related comorbidities, improved hemodynamics, and alleviated cardiac dysfunction, pulmonary vascular remodeling, myocardial hypertrophy, and fibrosis. BMS also suppressed cardiac fibroblasts (CFs) differentiation and downregulated the Smad3/TGFβ fibrotic signaling pathway in RV tissue, suggesting an anti‐fibrotic mechanism. These findings demonstrate that FABP4 serves as both a potential plasma biomarker for PH‐LHD severity and a therapeutic target. BMS ameliorates PH‐LHD by inhibiting RV fibrosis via modulation of CF differentiation into myofibroblasts, underscoring FABP4 as a promising intervention for PH‐LHD.