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

Area of Science:

• Hepatology
• Immunology
• Molecular Biology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) can advance to severe liver conditions like fibrosis and cancer.
• Macrophage dysregulation in the liver's immune microenvironment is implicated in MASLD pathogenesis.
• The specific roles of macrophages in MASLD development require further elucidation.

Purpose of the Study:

• To investigate the role of KIF13B in macrophage function during MASLD.
• To identify molecular mechanisms linking macrophages to MASLD progression.
• To uncover novel regulatory pathways and potential therapeutic targets for MASLD.

Main Methods:

• Analyzing KIF13B expression in macrophages from MASLD patients and mice.
• Investigating the impact of myeloid Kif13b deletion on diet-induced MASLD in mice.
• Elucidating the molecular interactions involving KIF13B, STT3A, CTSD, and THBS1 using proteasome degradation assays and protein interaction studies.
• Identifying upstream regulators of KIF13B through promoter binding analysis.

Main Results:

• KIF13B expression is downregulated in macrophages during MASLD.
• Loss of myeloid Kif13b exacerbates diet-induced MASLD in mice.
• Kif13b deficiency impairs STT3A degradation, increasing CTSD secretion and promoting liver lipid accumulation and inflammation.
• CTSD interacts with THBS1 on hepatocytes, contributing to MASLD.
• ZNF384 acts as a transcriptional activator for KIF13B, with its expression also reduced in MASLD.

Conclusions:

• A novel regulatory axis (ZNF384/KIF13B/STT3A/CTSD/THBS1) is identified, crucial for macrophage-hepatocyte communication in MASLD.
• This axis plays a significant role in MASLD progression.
• The identified pathway presents potential therapeutic targets for MASLD treatment.