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

Interleukin-1β (IL-1β) plays a central role in driving vascular inflammation and endothelial dysfunction, key processes in the development of atherosclerosis. While biologic therapies targeting IL-1β have shown clinical benefit, their high cost, injectable nature, and potential side effects limit their broader use. Therefore, there is a need to explore more accessible alternatives. In this study, we aimed to identify repurposed small-molecule inhibitors that can effectively modulate IL-1β signaling and protect endothelial function.

We used an integrated strategy combining computational and experimental approaches. Virtual screening, molecular docking, molecular dynamics simulations, and MM-PBSA analyses were performed to identify potential inhibitors targeting IL-1R1. The most promising candidates were then evaluated in vitro using endothelial cell models (HUVEC and EA.hy.926). Their effects were assessed through functional assays, including transendothelial electrical resistance (TEER), VE-cadherin immunofluorescence, and cell viability measurements.

Two FDA-approved drugs, radotinib and lomitapide, emerged as strong candidates with high binding affinity and stability toward IL-1R1, outperforming the reference inhibitor anakinra in computational analyses. Experimental validation showed that both compounds effectively reduced IL-1β-induced endothelial dysfunction. They restored barrier integrity, improved TEER values, and maintained VE-cadherin expression and localization. Importantly, both compounds exhibited low cytotoxicity and mitigated IL-1β-driven increases in endothelial permeability.

Our findings highlight radotinib and lomitapide as promising repurposed small-molecule inhibitors of IL-1β signaling. By preserving endothelial integrity and dampening inflammatory responses, these compounds may serve as cost-effective and orally available alternatives to current biologic therapies. Further in vivo and mechanistic studies are needed to advance their potential clinical application.