SIRT5 Deficiency Drives Cardiac Fibrosis via Metabolic Shift in Mice

Cardiac fibrosis remains a central pathological feature of heart failure, characterized by the excessive deposition of extracellular matrix that impairs ventricular compliance and electrical conduction. While traditional management focuses on neurohormonal blockade, the underlying epigenetic and metabolic shifts that drive fibroblast activation are increasingly recognized as critical therapeutic targets [1]. Chronic inflammation and oxidative stress within the myocardial microenvironment further exacerbate this remodeling process, involving the production of reactive species and lipid peroxidation products (the oxidative degradation of lipids) that trigger cellular damage [2, 3, 4]. These pathological changes involve active phenotypic transitions, such as epithelial-mesenchymal transition (a process where cells lose their organized structure to acquire a migratory, collagen-producing phenotype), and metabolic adaptations within resident cell populations [5, 6, 7]. A new study now identifies that SIRT5 (sirtuin 5) expression is significantly downregulated in the cardiac fibroblasts of patients with heart failure, leading to the succinylation of PCK2 (phosphoenolpyruvate carboxykinase 2) at the Lys489 residue, which drives a metabolic shift toward glycolysis and promotes fibrotic activation [8].