Osthole targets doublecortin like kinase 1 (DCLK1/DCAMKL1) in macrophages to inhibit NF‐κB‐mediated inflammation and alleviate atherosclerosis

BACKGROUND AND PURPOSE: Atherosclerosis is a chronic inflammatory disease. Targeting inflammatory pathways provides a promising avenue to treat atherosclerosis. Osthole (OS), isolated from the Cnidium plant, has been reported diverse pharmacological activities, including anti-cancer, anti-oxidant, neuroprotective, anti-osteoporosis and anti-inflammatory effects. However, the role on atherosclerosis and molecular targets of osthole remains unclear. We aimed to explore the anti-atherosclerosis role of osthole and investigate the underlying molecular mechanism. EXPERIMENTAL APPROACH: mice were fed with a high-fat diet (HFD) for 8 weeks to induce atherosclerosis. KEY RESULTS: mice. Mechanistically, protein microarray incubated with biotin-labelled osthole identified doublecortin like kinase 1 (DCLK1/DCAMKL1) as the top-ranked binding protein of osthole. Osthole directly bound to DCLK1 at I396 and L518 sites, inhibited the phosphorylation of DCLK1, and then prevented its interaction with inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ). Through targeting DCLK1, osthole suppressed NF-κB pathway activation and inflammatory responses in both MPMs and aortic lesions. CONCLUSION AND IMPLICATIONS: Taken together, our findings show the therapeutic potential of osthole against inflammatory atherosclerosis and establish a foundation for targeting DCLK1 therapy in atherosclerosis.