Group 2 pulmonary hypertension (PH) has no approved PH-targeted therapy. Metabolic remodelling, specifically a biventricular increase in pyruvate kinase muscle (PKM) isozyme 2 to 1 ratio, occurs in rats with group 2 PH induced by supra-coronary aortic banding (SAB). We hypothesize that increased PKM2/PKM1 is maladaptive and inhibiting PKM2 would improve right ventricular (RV) function. Male, Sprague-Dawley SAB rats were confirmed to have PH by echocardiography and then randomized to treatment with a PKM2 inhibitor (intraperitoneal shikonin, 2mg/kg/day) versus 5% DMSO (n=5/group) or small interfering RNA-targeting PKM2 (siPKM2) versus siRNA controls (n=7/group) by airway nebulization. Shikonin-treated SAB rats had milder PH (PAAT 32.1±1.3 vs 22.1±1.2ms, P=.0009) and lower RV systolic pressure (RVSP) (31.5±0.9 vs 55.7±1.9mmHg, P<.0001) versus DMSO-SAB rats. siPKM2 nebulization reduced PKM2 expression in the RV, increased PAAT (31.7±0.7 vs 28.0±1.3ms, P=.025), lowered RVSP (30.6±2.6 vs 42.0±4.0mm Hg, P=.032) and reduced diastolic RVFW thickness (0.69±0.04 vs 0.85±0.06mm, P=.046). Both shikonin and siPKM2 regressed PH-induced medial hypertrophy of small pulmonary arteries. Increases in PKM2/PKM1 in the RV contribute to RV dysfunction in group 2 PH. Chemical or molecular inhibition of PKM2 restores the normal PKM2/PKM1 ratio, reduces PH, RVSP and RVH and regresses adverse PA remodelling. PKM2 merits consideration as a therapeutic cardiac target for group 2 PH.