Restoring lysosomal proteostasis reverses steatohepatitis and fibrosis in experimental MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by progressive inflammation and fibrosis. Left untreated, MASH can progress to cirrhosis, hepatocellular carcinoma, and liver failure. MASH has become the leading indication for liver transplantation worldwide. While global prevalence is increasing, effective and mechanism-oriented therapies remain limited. Based on earlier independent studies showing that lysosomes are impaired and autophagy is dysregulated in MASH, our aim was to finely map autophagy dysfunction in an experimental mouse model of MASH and explore the capacity of a modulator of chaperone-mediated autophagy to mitigate the course of the disease. We effectively identified a number of markers whose expression was pathologically increased or decreased in various autophagy pathways. In vivo, pharmacological modulation with the phosphopeptide P140 -currently evaluated in phase III-clinical trials for lupus- corrected the expression of some of these markers and restored lysosomal and mitochondrial autophagy programs. It reduced steatohepatitis and fibrosis, and improved systemic inflammatory features without, however, broadly correcting metabolic parameters. Mechanistically, consistent with its established HSPA8 interaction, P140 restored lysosomal/autophagy markers, supporting modulation of this proteostasis network. Our data indicate that this pharmacological restoration of lysosomal proteostasis engages key transcriptional regulators (Mediator complex), leading to the selective remodeling of pro-fibrotic and inflammatory pathways. Collectively, we identified a coordinated disruption of lysosomal quality control networks across multiple autophagy pathways in a validated mouse model of advanced MASH. We established lysosomal autophagy as a druggable vulnerability in MASH and support therapeutic repositioning of P140 as a safe strategy to counter progressive liver diseases.