FKBP11 drives cardiomyocyte ferroptosis in HFpEF by destabilizing GPX4 via proteasomal degradation

Background Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases and lacks effective targeted therapies due to its complex pathophysiology. FK506-binding protein 11 (FKBP11), an endoplasmic reticulum–resident member of the FKBP family, is involved in protein folding and stress adaptation and has been implicated in oxidative stress–related metabolic disorders. However, its expression pattern in cardiomyocytes and its role in HFpEF progression remain unclear. Objective To investigate the role and underlying mechanisms of FKBP11 in the development of HFpEF. Methods FKBP11 global knockout mice were generated using CRISPR/Cas9 technology. HFpEF was induced by high-fat diet combined with L-NAME administration. Cardiac function was evaluated by echocardiography and hemodynamic analysis. Histological staining assessed myocardial fibrosis and hypertrophy, while heart failure markers were measured by qPCR and Western blotting. Single-cell RNA sequencing and immunofluorescence were used to determine FKBP11 localization. Cardiomyocyte-specific FKBP11 knockdown or overexpression was achieved via AAV9 delivery. Transcriptomic and proteomic analyses identified downstream pathways. Oxidative stress and lipid peroxidation were evaluated by DHE, 4-HNE staining, and measurement of MDA, GSH, and GSSG. A GPX4 allosteric activator was administered in vivo to determine whether ferroptosis targeting could reverse FKBP11-mediated cardiac dysfunction. Results FKBP11 expression was significantly upregulated in HFpEF hearts and predominantly localized in cardiomyocytes. Both global and cardiomyocyte-specific deletion of FKBP11 improved exercise tolerance and alleviated diastolic dysfunction, myocardial hypertrophy, and fibrosis. Omics analyses revealed enrichment of ferroptosis- and glutathione metabolism–related pathways after FKBP11 deletion, with increased SLC7A11 and GPX4 expression and reduced oxidative stress. In vitro, palmitic acid induced FKBP11 expression while suppressing SLC7A11 and GPX4, promoting oxidative stress and lipid peroxidation; these effects were reversed by FKBP11 knockdown. Mechanistically, FKBP11 directly interacted with GPX4, enhanced its ubiquitination, and promoted its degradation via the ubiquitin–proteasome pathway, thereby triggering ferroptosis. Pharmacological activation of GPX4 significantly attenuated oxidative stress and improved HFpEF phenotypes in FKBP11-overexpressing mice. Conclusion FKBP11 promotes HFpEF progression by facilitating GPX4 ubiquitination and degradation, leading to cardiomyocyte ferroptosis. Targeting the FKBP11–GPX4 axis may represent a potential therapeutic strategy for HFpEF.