Fbxo7 stabilizes PHGDH to maintain cardiac serine metabolism and prevent heart failure
Y Gong, X Wang, Zhezhe ChenAbstract
Background
Cardiac metabolic reprogramming is a key pathological feature of heart failure. Previous studies have found reduced serine content in failing hearts, yet the underlying molecular mechanisms remain incompletely understood. PHGDH (phosphoglycerate dehydrogenase) is the rate-limiting enzyme in the serine synthesis pathway, essential for maintaining cardiomyocyte hypertrophy. However, the regulatory mechanisms governing PHGDH stability in the myocardium and its relationship with heart failure have not been elucidated. This study aims to investigate whether the E3 ubiquitin ligase Fbxo7 influences cardiac metabolism and function by regulating PHGDH stability.
Methods
Single-nucleus RNA sequencing analysis was performed to delineate the expression patterns of Fbxo7 in human heart failure. Pressure overload was induced by transverse aortic constriction (TAC) in mice. Transcriptomic, proteomic, and metabolomic regulations were evaluated by RNA sequencing, mass spectrometry, and metabolomics, respectively. Cardiac-specific deletion of Fbxo7 was achieved by crossing floxed Fbxo7 mice with Myh6-Cre mice. AAV9 carrying cTnT promoter-driven Fbxo7 (AAV9-cTnT-Fbxo7) was administered to investigate its rescue effect in TAC-induced cardiac dysfunction.
Results
Fbxo7 levels were significantly decreased in hypertrophic hearts from heart failure patients and mice subjected to TAC. Fbxo7-cKO mice exhibited a pronounced heart failure phenotype following TAC surgery, characterized by impaired compensatory hypertrophy, ventricular dilation, and aggravated fibrosis. Mechanistically, Fbxo7 enhances PHGDH stability through ubiquitination. Loss of Fbxo7 led to reduced PHGDH protein levels, serine deficiency, suppressed mTORC1 pathway activity, and inhibited protein synthesis, ultimately driving the transition from compensatory cardiac hypertrophy to decompensated heart failure. Fbxo7 overexpression ameliorated heart failure in mice and increased myocardial serine content. Exogenous serine supplementation also partially rescued the heart failure phenotype in Fbxo7-cKO mice.
Conclusion
Our study demonstrates that Fbxo7 maintains the cardiac serine-mTOR-protein synthesis axis through non-canonical ubiquitination-mediated PHGDH stabilization, serving as a critical metabolic checkpoint for preserving compensatory hypertrophy under pressure overload. Targeting the Fbxo7-PHGDH pathway may offer a novel metabolic therapeutic strategy for heart failure.Fig1Fig2