LXRα agonists have attracted signifi cant attentiondue to their potential biological activities on promotingcholesterol effl ux. This study was designed to investigatewhether setosphapyrone C and D have potential lipid-loweringcapacity and the underlying mechanisms in vitro. Ourdata showed that setosphapyrone C and D had weak cytotoxicitycompared to the liver X receptor α (LXRα) agonistT0901317. In RAW 264.7 macrophages, setosphapyroneC and D signifi cantly enhanced [ 3 H]-cholesterol effl ux by~ 21.3% and 32.4%, respectively; furthermore, setosphapyroneC and D enhanced the protein levels of ATP-bindingcassette transporter (ABC) A1 and LXRα by 58% and 69%,and 60% and 70% (8 μM), respectively; however, they had noeff ect on the protein levels of ABCG1 and scavenger receptorB type 1; additionally, they had minor eff ect on the mRNAexpression of lipogenic genes. Of note, setosphapyrone C and D signifi cantly enhanced LXRα/ABCA1pathway inmice primary macrophages. In BRL cells, setosphapyroneC and D signifi cantly improved the protein levels of ABCA1and ABCG1; setosphapyrone D signifi cantly enhanced theprotein expression of low-density lipoprotein. Collectively,setosphapyrone C and D with weak cytotoxicity exhibitedeff ective lipid-lowering eff ect via enhancing LXRα/ABCpathways. Setosphapyrones possess potential applicationfor the treatment of hyperlipidemic diseases.