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Small molecule inhibition of with no lysine kinase 1 (WNK1) (WNK463) signaling activates adenosine monophosphate-activated protein kinase signaling and mitigates membrane enrichment of glucose transporters 1 and 4, which decreases protein O-GlcNAcylation and glycation. Quantitative proteomics of right ventricular (RV) mitochondrial enrichments shows WNK463 prevents down-regulation of several mitochondrial metabolic enzymes. and metabolomics analysis suggests multiple metabolic processes are corrected. Physiologically, WNK463 augments RV systolic and diastolic function independent of pulmonary arterial hypertension severity. Hypochloremia, a condition of predicted WNK1 activation in patients with pulmonary arterial hypertension, is associated with more severe RV dysfunction. These results suggest WNK1 may be a druggable target to combat metabolic dysregulation and may improve RV function and survival in pulmonary arterial hypertension., Competing Interests: Dr Prisco was supported by the National Institutes of Health (NIH) (F32 HL154533 and T32 HL144472), a University of Minnesota Clinical and Translational Science award (NIH UL1 TR002494), and a University of Minnesota Medical School Academic Investment Educational Program Grant. Dr Thenappan was supported by the Cardiovascular Medical Research and Education Fund and the University of Minnesota Futures Grant. Dr Prins was supported by National Institutes of Health (K08 HL140100), the Cardiovascular Medical Research and Education Fund, a Lillehei Heart Institute Cardiovascular Seed Grant, the University of Minnesota Faculty Research Development Grant, the United Therapeutics Jenesis Award, and an American Lung Association Innovative Award (IA-816386). Dr Thenappan has served on advisory boards for Actelion, United Therapeutics, Altavant Sciences, and Aria CV; and has received research funding for clinical trials from United Therapeutics, Aria CV, Gossimer Bio, and Acceleron. Dr Prins has served on advisory boards for Actelion and Edwards; and has received grant funding from United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)