Urea cycle fumarate limits fibrosis post-myocardial infarction by reducing fibroblast mitochondrial adenosine triphosphate production
Cardiovascular Research
Could restricting fibroblast energy limit adverse remodelling after myocardial infarction (MI)? Zhao and colleagues reframe persistent post-MI fibrosis as an energy-dependent cellular state, uncovering an unexpected metabolic bridge between the urea- and Krebs cycles.
The sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin activates the N-acetylglutamate-argininosuccinate lyase–fumarate axis; accumulating fumarate restrains mitochondrial ATP production, thereby reducing fibroblast activation, collagen secretion and cardiac fibrosis.
Supported by metabolomics, metabolic-flux analysis, genetic experiments and validation in human cardiac fibroblasts, these findings position fibroblast energetics – not only profibrotic signalling – as a potential therapeutic target for limiting pathological remodelling while preserving essential infarct repair.
