TSP50 attenuates metabolic dysfunction-associated steatotic liver disease via SCD1 degradation-mediated suppression of hepatocyte lipogenesis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to chronic liver disease worldwide, yet the molecular mechanisms driving its pathogenesis remain incompletely defined. Although dysregulated hepatic lipogenesis is a well-established driver of MASLD progression, the role of testes-specific protease 50 (TSP50)—an enzyme with demonstrated oncogenic functions in multiple cancers—in hepatic lipid metabolism and its potential involvement in the development of MASLD remains unexplored. The study utilized the STelic Animal Model (STAM) along with high-fat/high-cholesterol plus fructose (HFF) and methionine-choline deficient (HFMCD) dietary models to evaluate the functional role of TSP50 in MASLD progression. Hepatocyte-specific knockout and AAV-mediated TSP50 reconstitution were performed to assess cell-autonomous effects. Mechanistic insights were gained through biochemical analyses of lipid metabolism pathways and protein interaction studies. TSP50 deficiency markedly accelerated MASLD progression across all experimental models, promoting hepatic steatosis, inflammation and fibrosis while increasing susceptibility to hepatocellular carcinoma (HCC). Conversely, TSP50 supplementation exerted protective effects against MASLD development. Furthermore, we identified a novel regulatory mechanism whereby TSP50 directly interacts with and degrades stearoyl-CoA desaturase 1 (SCD1) through its catalytic hydrolase activity, thereby suppressing de novo lipogenesis. The inhibitor of SCD1 rescued hepatic TSP50 knockout induced lipid accumulation and liver injury during MASLD. Our study reveals the role of TSP50 in hepatic lipid metabolism, identifying it as a novel regulator of hepatic de novo lipogenesis that exerts protective effects against MASLD through catalytic degradation of SCD1. These findings not only advance our understanding of MASLD pathogenesis but also offer novel insights for developing therapeutic strategies.