NSD2 mediated H3K36me2 promotes pulmonary arterial hypertension by recruiting FOLR1 and metabolism reprogramming

Abstract

Pulmonary artery hypertension (PAH) is characterized by a cancer-like metabolic shift towards aerobic glycolysis. Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone methyltransferase, has been implicated in PAH, yet its precise role remains unclear. In this study, we induced PAH in C57BL/6 mice using monocrotaline (MCT) and observed increased FOLR1 expression in PAH tissues, which was suppressed by NSD2 knockdown. Silencing NSD2 or FOLR1 inhibited the proliferation and migration of pulmonary artery endothelial cells (PAECs) and alleviated PAH phenotypes, right ventricular dysfunction, and pulmonary artery remodeling. Mechanistically, NSD2 knockdown prevented nuclear translocation of FOLR1 and its interaction with H3K36me2. Metabolic analysis revealed that NSD2 or FOLR1 knockdown reversed the increased oxygen consumption rate, extracellular acidification rate, glucose consumption, lactate production, and G6PD activity in MCT-treated PAECs. Furthermore, NSD2 or FOLR1 silencing decreased the expression of key glycolytic genes (HK2, TIGAR, and G6PD) by suppressing their promoter activity and weakening the interaction between FOLR1/H3K36me2 and these gene promoters. Our findings suggest that NSD2-mediated H3K36me2 recruits FOLR1 to promote PAH, and FOLR1 acts as a transcriptional factor to upregulate glycolytic gene expression in PAECs.