Long-lasting recombinant HEXA treatment improves hepatic steatosis and glycemic control in mild, but not severe, metabolic dysfunction-associated steatohepatitis

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing at an alarming rate. To date, only one therapy has been provisionally approved for the treatment of MASH and liver fibrosis, and novel strategies are urgently needed. In addition, the frequent coexistence of MASH and type 2 diabetes has further intensified interest in devising comprehensive therapies to simultaneously tackle both diseases. We have recently shown that increasing hepatic and/or circulating levels of hexosaminidase A (HEXA), a lysosomal enzyme that remodels GM2 to GM3 gangliosides within lipid rafts, offers therapeutic benefits for metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. Taking advantage of the MUP-uPA mouse model of MASH, including both wild-type (WT) mice with mild MASH and MUP-uPA mice with severe MASH and fibrosis, we show that biweekly treatment with a long-lasting HEXA-FC analog improves features of MASLD, including hepatic steatosis and hepatocyte ballooning, in mice with mild MASH, as well as glycemic control across both mouse models. Mechanistically, HEXA-FC enhances hepatic fatty acid oxidation and peripheral glucose disposal while not impacting endogenous glucose production. Together, these outcomes suggest that while HEXA-FC treatment may offer therapeutic benefits in mild MASH and insulin resistance, it is ineffective against severe MASH and liver fibrosis.<b>NEW & NOTEWORTHY</b> The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes is increasing. Here, we show that chronic FC-HEXA recombinant protein treatment reduces hepatic lipid accumulation and improves blood glucose control in mice with mild MASH and insulin resistance.