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Background: Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H2S)., Objectives: This study evaluated H2S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H2S on HFpEF severity through alterations in endogenous H2S production and pharmacological supplementation., Methods: HFpEF patients and two rodent models of HFpEF ("two-hit" L-NAME + HFD mouse and ZSF1 obese rat) were evaluated for H2S bioavailability. Two cohorts of two-hit mice were investigated for changes in HFpEF pathophysiology: (1) endothelial cell cystathionine-γ-lyase (EC-CSE) knockout; (2) H2S donor, JK-1, supplementation., Results: H2S levels were significantly reduced (i.e., 81%) in human HFpEF patients and in both preclinical HFpEF models. This depletion was associated with reduced CSE expression and activity, and increased SQR expression. Genetic knockout of H2S -generating enzyme, CSE, worsened HFpEF characteristics, including elevated E/e' ratio and LVEDP, impaired aortic vasorelaxation and increased mortality. Pharmacologic H2S supplementation restored H2S bioavailability, improved diastolic function and attenuated cardiac fibrosis corroborating an improved HFpEF phenotype., Conclusions: H2S deficiency is evident in HFpEF patients and conserved across multiple HFpEF models. Increasing H2S bioavailability improved cardiovascular function, while knockout of endogenous H2S production exacerbated HFpEF pathology and mortality. These results suggest H2S dysregulation contributes to HFpEF and increasing H2S bioavailability may represent a novel therapeutic strategy for HFpEF., Highlights: H2S deficiency is evident in both human HFpEF patients and two clinically relevant models.Reduced H2S production by CSE and increased metabolism by SQR impair H2S bioavailability in HFpEF.Pharmacological H2S supplementation improves diastolic function and reduces cardiac fibrosis in HFpEF models.Targeting H2S dysregulation presents a novel therapeutic strategy for managing HFpEF.