With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension

•Small molecule inhibition of WNK1 (WNK463) signaling mitigates upregulation of the membrane glucose channels GLUT1 and GLUT4, restores levels of several glucose metabolites, and decreases protein O-GlcNAcylation and glycation in the RV.•Quantitative proteomics of RV mitochondrial enrichments shows WNK463 treatment prevents down-regulation of several mitochondrial enzymes in the tricarboxylic acid cycle, fatty acid oxidation pathway, and the electron transport chain complexes.•Integration of proteomics and metabolomics analysis suggests WNK463 reduces glutaminolysis induction and lipotoxicity caused by impaired mitochondrial fatty acid oxidation.•WNK463 augments RV systolic and diastolic function independent of PAH severity.•Hypochloremia, a condition of predicted WNK1 activation in patients with PAH, is associated with more severe RV dysfunction.