Licochalcone B alleviates atherosclerosis by inhibiting endothelial inflammation via targeting the KEAP1/NRF2/NF-κB...

Atherosclerosis is a chronic inflammatory disorder of the arterial subendothelium that remains a major clinical challenge. Licochalcone B (LCB), a licorice-derived flavonoid, has been documented to display anti-inflammatory effects; however, its therapeutic potential for atherosclerosis remains unknown.

To evaluate the efficacy of LCB against atherosclerosis and to uncover the mechanisms involved.

To establish an atherosclerosis model, ApoE^-/- mice were fed a high-fat diet, after which they received treatment with either LCB at two different doses or simvastatin for 8 weeks. Therapeutic efficacy was evaluated via histological analysis. In vitro studies employing transcriptome sequencing, Western blotting, immunofluorescence, cellular thermal shift assay, surface plasmon resonance, molecular docking, and RNA interference were conducted to examine the anti-inflammatory mechanisms of LCB in endothelial cells.

LCB treatment significantly attenuated atherosclerotic progression, as evidenced by reduced plaque area and increased plaque stability, along with suppression of endothelial inflammation in ApoE^-/- mice. Mechanistically, LCB directly targeted KEAP1 in endothelial cells, promoting its autophagic degradation. This event initiated an NRF2-dependent antioxidant response, subsequently suppressed NF-κB p65 phosphorylation at Ser276, and ultimately downregulated VCAM1 and ICAM1 in inflamed endothelial cells.

This study offers the first demonstration that LCB attenuates atherosclerosis through the suppression of endothelial inflammation by targeting the KEAP1/NRF2/NF-κB axis. Notably, LCB exhibited no hepatotoxicity or nephrotoxicity, underscoring its suitability as a safe pharmacological agent for atherosclerotic cardiovascular disease.