Abstract Body: Background: Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and is strongly associated with cardiometabolic disease. Conditions such as obesity and metabolic dysfunction–associated steatotic liver disease (MASLD) frequently coexist with HFpEF, yet the mechanisms linking cardiometabolic stress to cardiac dysfunction remain poorly understood. Identifying conserved molecular programs underlying cardiometabolic cardiac remodeling may reveal new therapeutic targets. Hypothesis: We hypothesized that cardiometabolic stress induces conserved cardiac transcriptional programs that drive diastolic dysfunction across cardiometabolic disease states. Methods: Mice were subjected to three complementary cardiometabolic disease models including HFpEF (two-hit metabolic stress), choline-deficient amino acid-defined high-fat diet (MASLD), and Western diet. Cardiac function was assessed by echocardiography and myocardial fibrosis by histology. Bulk RNA sequencing of cardiac tissue across models identified conserved cardiometabolic transcriptional responses. Candidate mediators were prioritized and therapeutically targeted in the HFpEF model. Results: Despite distinct metabolic and hepatic pathologies, all cardiometabolic models converged on cardiac fibrosis and diastolic dysfunction. Cross-model transcriptomic analysis identified Serpine1, encoding plasminogen activator inhibitor-1 (PAI-1), as one of the most consistently upregulated cardiac genes. Pathway analysis linked Serpine1 induction to lipid metabolism, extracellular matrix remodeling, and inflammatory signaling associated with cardiometabolic injury. Notably, PAI-1 is elevated in HFpEF patients and associated with adverse outcomes. Pharmacologic PAI-1 inhibition significantly improved HFpEF diastolic function, reducing E/e′ and myocardial fibrosis compared with vehicle-treated controls (p<0.05). Conclusions: These findings reveal that diverse cardiometabolic disease states converge on conserved cardiac remodeling programs that drive diastolic dysfunction. Targeting shared mediators of this remodeling may represent a unifying therapeutic strategy for cardiometabolic HFpEF.