Cathepsin D-driven IL2RG–JAK2 signal hijacking disrupts hepatic insulin action

This study investigates the roles of cathepsin D (CTSD) in the underlying mechanisms involving HIR and impaired glucose homeostasis. Samples from people/mice with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), as well as HIR cellular models, were used to assess mRNA expression, protein expressions, and activity of CTSD. RNA sequencing data from hepatocytes revealed the potential mechanism of CTSD-induced HIR. The authors constructed plasmids for CTSD overexpression and knockdown to verify the effects and mechanisms of CTSD in HIR. Administration of the CTSD inhibitor Pepstatin A (PepA) to mice with obesity/MASLD explored the preventive effect of targeting CTSD on prediabetes. Significant increases in mRNA expression, protein levels, and activity of CTSD were observed in individuals and mice with obesity/MASLD, as well as in HIR cell models, compared to controls. Increased CTSD or overexpressing CTSD triggered HIR mediated by the IL2RG–JAK2 axis, disturbing hepatic insulin signaling transduction. Inhibiting CTSD with PepA or knocking down CTSD improved HIR and rebalanced glucose metabolism in mice with obesity/MASLD and HIR cell models. These findings implicate that increased CTSD suppresses hepatic insulin sensitivity via activating the IL2RG–JAK2–STAT3 axis, highlighting CTSD inhibition as an attractive preventative strategy for prediabetes.