Isolinderalactone attenuates atherosclerosis through inhibiting NF-κB-mediated inflammation in macrophages

Atherosclerosis is a chronic inflammatory disease affecting medium and large arteries, characterized by lipid ectopic deposition in arterial wall, whose pathogenesis is closely associated with persistent excessive inflammatory responses. Isolinderalactone (ILL), the primary active sesquiterpene lactone component derived from the traditional Chinese medicine Lindera aggregata, has been demonstrated to possess significant anti-inflammatory and anti-proliferative activities. This study aims to investigate the therapeutic potential of ILL in atherosclerosis and its underlying molecular mechanisms. ApoE^-/- mice were fed with a high-fat/cholesterol diet for 8 weeks to induce an atherosclerosis model and administering different doses of ILL (5, 10 mg/kg, intraperitoneal injection every other day), we found that ILL significantly reduced the size and foam of atherosclerotic lesions in HFD-fed ApoE^-/- mice. Furthermore, ILL inhibited inflammatory cell infiltration in the aortic lesions tissue. In vitro experiments further revealed that ILL (10, 20 μM) effectively suppressed the uptake of oxLDL in macrophages. Bioinformatics analysis of RNA-seq (macrophages) showed that ILL exerts a protective effect against atherosclerosis by inhibiting the NF-κB signaling pathway. In vitro and vivo data systematically elucidate that ILL reduces expression of pro-inflammatory factors and scavenger receptors by modulating the NF-κB signaling pathway. This study suggests that ILL may be a potential therapeutic candidate for delaying the progression of atherosclerosis and providing a new strategy for the treatment of atherosclerosis.