Gut Metabolite Indole‐3‐Propionic Acid Regulates Macrophage Autophagy Through PPT1 Inhibiting Aging‐Related Myocardial Fibrosis

Lyz2-cre mice, it is demonstrated that macrophage-specific deletion of PPT1 significantly reduced cardiac inflammation and myocardial fibrosis in aged mice. Furthermore, PPT1 silencing in macrophages reduced the expression of myocardial fibrosis markers in vitro. Mechanistically, IPA regulated PPT1 expression to modulate the PI3K-AKT-mTOR pathway, thereby restoring autophagic activity in senescent macrophages and suppressing both inflammation and aging-related myocardial fibrosis. Additionally, IPA influenced the cGAS-STING signaling pathway to regulate PPT1 expression. These findings demonstrate that IPA inhibits PPT1, activates autophagy in macrophages, and mitigates aging-related myocardial fibrosis.