Myeloid KIF13B suppresses the STT3A/CTSD/THBS1 axis to prevent MASH

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a critical pathological stage that can progress to liver fibrosis and hepatocellular carcinoma, and its development is closely associated with dysregulation of the hepatic immune microenvironment, in which macrophages make a crucial contribution. However, the precise mechanisms mediated by macrophages underlying the pathogenesis of this disease remain incompletely understood. APPROACH AND RESULTS: In the present study, we demonstrate that under MASLD conditions, KIF13B expression is markedly downregulated in monocyte-derived macrophages, and deletion of myeloid-derived Kif13b predisposes mice to diet-induced MASLD. Mechanistically, Kif13b deficiency impairs proteasome-dependent degradation of the glycosyltransferase STT3A in macrophages, thereby enhancing cathepsin D (CTSD) glycosylation and secretion to promote lipid accumulation and inflammatory responses in livers. Further analyses reveal that the detrimental effects of CTSD depend on its interaction with the hepatocyte membrane protein Thrombospondin 1 (THBS1). In addition, we identify the transcription factor ZNF384 as a potential upstream regulator of KIF13B gene through directly binding to its promoter for the transcriptional activation, which expression is also significantly downregulated in the context of MASLD. CONCLUSIONS: Collectively, our study establishes a novel regulatory axis, ZNF384/KIF13B/STT3A/CTSD/THBS1, essential for macrophage-hepatocyte crosstalk during MASLD progression and provides potential therapeutic targets for the treatment of MASLD.