SMOC2 accelerates myocardial fibrosis following myocardial infarction by promoting lipid peroxidation through inhibition of the LKB1/AMPKα/FOXO3 pathway

SMOC2 accelerates myocardial fibrosis following myocardial infarction by promoting lipid peroxidation through inhibition of the LKB1/AMPKα/FOXO3 pathway: Upon MI injury, SMOC2 is upregulated and secreted by cardiac fibroblasts. Extracellular SMOC2 binds to Integrin αvβ5 on the cell membrane, which subsequently inhibits the LKB1/AMPKα signaling axis. This inhibition suppresses FOXO3 activity, leading to impaired antioxidant defense and the accumulation of lipid peroxides. The resulting metabolic disorders can activate fibroblasts, accelerating myocardial fibrosis after myocardial infarction. • Myocardial infarction and hypoxia/reoxygenation markedly increased SMOC2 expression in cardiac fibroblasts. • SMOC2 overexpression aggravated myocardial injury, inflammation, and fibrosis, whereas fibroblast-specific deletion alleviated these effects and improved cardiac function. • SMOC2 interacted with integrin αvβ5 to inhibit the LKB1/AMPKα/FOXO3 signalling pathway, suppressing antioxidant defense and promoting lipid peroxidation–driven oxidative stress. • RNA-seq and metabolomic analyses consistently revealed SMOC2-associated lipid metabolic disturbances. • Targeting SMOC2 or activating the AMPKα/FOXO3 axis may represent a potential strategy to mitigate maladaptive cardiac remodelling after MI. Myocardial infarction (MI) initiates a cascade of pathological events leading to cardiac remodeling, characterised by abnormal activation of cardiac fibroblasts, excessive extracellular matrix deposition, and progressive ventricular fibrosis, all of which contribute to heart failure. The secreted modular calcium-binding protein 2 (SMOC2), an extracellular matrix-associated protein, has been implicated in several fibrotic diseases. However, its specific role and underlying mechanisms in post-MI cardiac fibrosis remain largely undefined. This study aimed to investigate the role of SMOC2 in myocardial remodeling following MI and to elucidate the molecular mechanisms by which SMOC2 influences cardiac fibroblast activation, fibrosis, and cardiac dysfunction. Using a mouse model of left anterior descending artery (LAD) ligation and neonatal rat cardiac fibroblasts (NRCFs) subjected to hypoxia/reoxygenation (H/R), we observed a significant upregulation of SMOC2 expression after MI and in fibroblasts under H/R stress. Fibroblast-specific SMOC2 overexpression aggravated myocardial injury, inflammation, and fibrosis, whereas SMOC2 knockout markedly alleviated these effects and improved cardiac function. Mechanistically, SMOC2 interacted with integrin αvβ5 to inhibit the LKB1/AMPKα/FOXO3 signalling pathway, leading to reduced antioxidant defence, enhanced lipid peroxidation, and elevated oxidative stress. Integrated RNA sequencing and metabolomic analyses consistently revealed that SMOC2 disrupted lipid metabolism during cardiac remodeling. SMOC2 promotes cardiac injury and fibrosis following MI by suppressing the LKB1/AMPKα/FOXO3 signalling pathway through interaction with integrin αvβ5, thereby enhancing lipid peroxidation and oxidative stress. These findings suggest that targeting SMOC2 or reactivating the AMPKα/FOXO3 axis may serve as a potential therapeutic strategy to mitigate maladaptive cardiac remodeling after myocardial infarction.