Exosome‐Delivered eNAMPT From Exercise Activates SIRT1 to Counteract Age‐Related Hepatic Steatosis and Fibrosis

ABSTRACT Aging is a major independent risk factor for the development and progression of metabolic dysfunction‐associated steatotic liver disease (MASLD); however, effective therapeutic strategies for this population remain limited. Here, we established a model of aging‐associated MASLD by subjecting aged mice to a long‐term high‐fat diet (HFD), which recapitulated key disease features including progressive hepatic steatosis, inflammation, insulin resistance, and fibrosis. A 6‐week exercise intervention markedly ameliorated these pathologies by restoring insulin sensitivity and suppressing TGF‐β/Smad‐mediated fibrotic signaling. We identified exercise‐derived exosomes (Exercise‐Exos) as primary mediators of these benefits. Western blot analysis revealed that extracellular nicotinamide phosphoribosyltransferase (eNAMPT) was markedly enriched in Exercise‐Exos compared to those from sedentary controls. Delivery of exosomal eNAMPT activated the hepatic SIRT1‐autophagy axis, restored autophagic flux, and inhibited epithelial‐mesenchymal transition (EMT). These effects were demonstrated by an increased LC3‐II/LC3‐I ratio, reduced p62 accumulation, downregulation of mesenchymal markers (α‐SMA, Vimentin), and upregulation of the epithelial marker E ‐cadherin. Furthermore, Exercise‐Exos treatment significantly reduced collagen deposition. Critically, all protective effects were abolished upon pharmacological inhibition of SIRT1 with EX‐527, establishing the necessity of the eNAMPT‐NAD + ‐SIRT1 cascade. Collectively, our results elucidate a novel exosome‐mediated pathway through which exercise mitigates age‐related liver disease, positioning exosomal eNAMPT as a promising therapeutic agent and exercise mimetic for MASLD.