Targeting ICAM and VCAM in MASH: The Role of Nintedanib and Dasatinib in Reducing Inflammation, Fibrosis, and Growth Factor Expression in Liver Spheroids

Background: ICAM and VCAM, key adhesion molecules, play crucial roles in MASH by mediating immune cell infiltration and inflammation through Kupffer and endothelial cell interactions. These molecules, along with growth factors like VEGF and PDGF, drive fibrosis and liver damage, making them essential therapeutic targets.

Materials and Methods: Liver spheroids were generated under control and MASH conditions. ELISA measured ICAM, VCAM, VEGF, PDGF, IL-1β, IL-6, and TNF-α on Days 8 and 12. Immunohistological staining, including Nile red for steatosis, Collagen III for fibrosis, and Sirius Red for fibrotic tissue, was also performed. Spheroids were treated with Dasatinib (0.01 µM, 0.1 µM, 1 µM) and Nintedanib (0.1 µM, 0.5 µM, 1 µM) to assess their effects on adhesion molecules, growth factors, cytokines, and fibrotic markers.

Results: MASH spheroids showed significantly elevated ICAM, VCAM, VEGF, and PDGF levels. Nintedanib reduced ICAM at 0.5 µM and VCAM at 1 µM, while Dasatinib reduced both molecules at 0.1 µM and 1 µM, with the strongest VCAM effect at 1 µM. VEGF and PDGF were downregulated by both drugs, particularly at higher concentrations. IL-1β, IL-6, and TNF-α were significantly reduced after treatment with both drugs, with Dasatinib showing the greatest effect on pro-inflammatory cytokines.

Conclusion: Nintedanib and Dasatinib effectively downregulate ICAM, VCAM, pro-inflammatory cytokines, and growth factors in MASH spheroids. Nintedanib is more effective for ICAM reduction, while Dasatinib shows stronger effects on VCAM, VEGF, PDGF, and cytokines. Targeting these pathways could provide therapeutic benefits in MASH treatment.

Publication History

Article published online:
20 January 2025