Autophagy-regulating bioactive nanoparticle alleviates MASH via gut–liver axis-mediated mitochondria/cAMP/GLP1 pathway

Chronic exposure of the liver to diverse insults can lead to metabolic dysfunction-associated steatohepatitis (MASH), a complex metabolic disorder characterized by hepatic steatosis and inflammation, often accompanied by progressive fibrosis, intestinal barrier dysfunction, and intestinal endocrine imbalance. No approved pharmacotherapies effectively treat MASH largely because of the difficulty in reversing fibrosis and restoring extracellular matrix homeostasis. Managing intestinal barrier dysfunction and GLP1 secretion has emerged as a promising therapeutic strategy against the progression of metabolic-associated fatty liver (MAFL) to MASH. This study presents MSN@HTL, fabricated using trehalose and temsirolimus on mesoporous silica nanoparticles (MSNs) and encapsulated with sodium alginate using an electrostatic spraying system. After oral administration, MSN@HTL protects against intestinal barrier injury and GLP1 secretion, consequently inhibiting the progression of MAFL. MSN@HTL stimulated intestinal stem cell self-renewal, proliferation, and GLP1 secretion. Mechanistically, MSN@HTL induces lysosomal autophagy to recycle disrupted mitochondria, increasing mitochondrial fusion and energy metabolism, elevating cAMP concentration, and inducing PKA phosphorylation-mediated intestinal barrier revision and GLP1 secretion, thereby impairing MAFL-to-MASH progression. Given its availability and functionality, our study demonstrates the potential of MSN@HTL as a pharmaceutical agent for managing MAFL-to-MASH progression via the mitochondria/cAMP/PKA signaling pathway in humans.