Naringin affects VEGFC/TGF-β1 to mediate intercellular communication in MASH through coordinated Src and p38 MAPK...

Area of Science:

• Hepatology and Immunology
• Molecular Mechanisms of Disease
• Fibrosis Research

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis pathogenesis involves complex intercellular signaling.
• Previous research identified hepatocyte-derived vascular endothelial growth factor C (VEGFC) in monocyte recruitment to fibrotic foci.
• The intracellular signaling pathways linking VEGFC-mediated recruitment to fibrogenic output in MASH remained undefined.

Purpose of the Study:

• To elucidate the intracellular signaling mechanism (
• How
• ) by which VEGFC drives MASH fibrosis.
• To investigate the therapeutic potential of naringin (NAR) in targeting this pathway.

Main Methods:

• Utilized diet-induced MASH mouse models and hepatocyte-specific Vegfc knockout (Vegfc^△hep) mice.
• Administered naringin (NAR) and a vascular endothelial growth factor receptor-3 (VEGFR3) inhibitor (SAR131675).
• Analyzed macrophage polarization, intracellular signaling pathways (Src/p38 MAPK), and cytokine production (TGF-β1) in vitro and in vivo.

Main Results:

• Both NAR and SAR131675 treatment attenuated MASH, liver steatosis, inflammation, and fibrosis.
• VEGFC-VEGFR3 signaling activates the Src/p38 MAPK pathway in macrophages, promoting a pro-fibrotic phenotype.
• This pathway drives transforming growth factor-β (TGF-β1) production, leading to hepatic stellate cell (HSC) activation and fibrosis.

Conclusions:

• The study defines the complete VEGFC-VEGFR3-Src/p38 MAPK-TGF-β1 signaling axis in MASH fibrosis.
• Naringin (NAR) effectively targets this axis, offering a potential therapeutic strategy for MASH fibrosis.
• Understanding this mechanism provides critical insights into fibrogenesis and potential drug targets.