Enhancing Natural Product Therapy with PROTACs: Targeted Degradation of TLR4 Confers Potent Endothelial Protection

Abstract TLR4-MyD88-mediated endothelial dysfunction drives cardiovascular disease. To overcome the weak efficacy of ferulic acid, we synthesized six ferulic acid-based PROTAC derivatives. Migration and TLR4 expression assays in HUVECs identified FP-4 as lead. FP-4 induced the targeted degradation of TLR4, suppressing the TLR4/MyD88-NF-κB pathway and downstream TNF-α, ICAM-1, and VCAM-1. Protection was validated in zebrafish. This expands PROTAC beyond oncology and offers a framework for natural product-derived cardiovascular therapy.