Costunolide alleviates atherosclerosis in high-fat diet-fed ApoE−/− mice through covalently binding to IKKβ and inhibiting NF-κB-mediated inflammation

Zhu-qi Huang1,2,3, Wu Luo1,2,3, Wei-xin Li1, Pan Chen1, Zhe Wang4, Rui-jie Chen4, Yi Wang1, Wei-jian Huang3, Guang Liang1,2,3
1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
2 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 311399, China
3 Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
4 Department of Pharmacy, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
Correspondence to: Wei-jian Huang:, Guang Liang:,
DOI: 10.1038/s41401-022-00928-0
Received: 25 March 2022
Accepted: 26 May 2022
Advance online: 16 June 2022


Costunolide (CTD) is a sesquiterpene lactone isolated from costus root and exhibits various biological activities including anti- inflammation. Since atherosclerosis is a chronic inflammatory disease, we herein investigated the anti-atherosclerotic effects of CTD and the underlying mechanism. Atherosclerosis was induced in ApoE−/− mice by feeding them with a high-fat diet (HFD) for 8 weeks, followed by administration of CTD (10, 20 mg ·kg−1·d−1, i.g.) for 8 weeks. We showed that CTD administration dose- dependently alleviated atherosclerosis in HFD-fed ApoE−/− mice. Furthermore, we found that CTD dose-dependently reduced inflammatory responses in aortas of the mice, as CTD prevented infiltration of inflammatory cells in aortas and attenuated oxLDL uptake in macrophages, leading to reduced expression of pro-inflammatory and pro-fibrotic molecules in aortas. Similar results were observed in oxLDL-stimulated mouse primary peritoneal macrophages (MPMs) in vitro. We showed that pretreatment with CTD (2.5, 5. 10 μM) restrained oxLDL-induced inflammatory responses in MPMs by blocking pro-inflammatory NF-κB/p65 signaling pathway. We further demonstrated that CTD inactivated NF-κB via covalent binding to cysteine 179 on IKKβ, a canonical upstream regulator of NF-κB, reducing its phosphorylation and leading to conformational change in the active loop of IKKβ. Our results discover IKKβ as the target of CTD for its anti-inflammatory activity and elucidate a molecular mechanism underlying the anti-atherosclerosis effect of CTD. CTD is a potentially therapeutic candidate for retarding inflammatory atherosclerotic diseases.
Keywords: atherosclerosis; costunolide; inflammation; IKK; NF-κB; IKKβ

Article Options

Download Citation

Cited times in Scopus