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

Abstract Cardiac fibrosis, a key pathological feature of cardiac remodeling, is a major contributor to mortality in older patients with heart failure. The underlying mechanisms are complex, involving alterations in intercellular communication and chronic inflammation. This study investigates the role of indole‐3‐propionic acid (IPA) in aging‐related myocardial fibrosis and its regulatory effects on autophagy through palmitoyl‐protein thioesterase 1 (PPT1). Here, plasma levels of IPA, a tryptophan‐derived metabolite, are found to be reduced in older patients with heart failure, and this reduction is associated with deteriorating cardiac function. Notably, IPA supplementation significantly attenuated aging‐related myocardial fibrosis. PPT1, a lysosomal enzyme involved in autophagy, is upregulated in macrophages during aging. IPA reversed aging‐induced increase in PPT1 expression. Using PPT1 flox/flox 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.