Modulating IL-1β-induced pro-atherogenic endothelial responses through drug repurposing

Area of Science:

• Cardiovascular Science
• Pharmacology
• Molecular Biology

Background:

• Interleukin-1β (IL-1β) drives vascular inflammation and endothelial dysfunction, contributing to atherosclerosis.
• Current biologic therapies targeting IL-1β are effective but costly and invasive.
• Accessible small-molecule inhibitors are needed to modulate IL-1β signaling and preserve endothelial function.

Purpose of the Study:

• Identify repurposed small-molecule drugs targeting IL-1β signaling.
• Evaluate their efficacy in protecting endothelial function.

Main Methods:

• Integrated computational (virtual screening, docking, simulations) and experimental approaches.
• In vitro evaluation using endothelial cell models (HUVEC, EA.hy.926).
• Functional assays including TEER, VE-cadherin immunofluorescence, and cell viability.

Main Results:

• Radotinib and lomitapide showed high binding affinity to IL-1R1 in silico.
• Both compounds reduced IL-1β-induced endothelial dysfunction in vitro.
• They restored barrier integrity, improved TEER, and maintained VE-cadherin expression with low cytotoxicity.

Conclusions:

• Radotinib and lomitapide are promising repurposed inhibitors of IL-1β signaling.
• These compounds preserve endothelial integrity and reduce inflammation.
• They represent potential cost-effective, orally available alternatives to biologic therapies.