Celastrol is a triterpene derived from the traditional Chinese medicine Tripterygium wilfordii Hook f,which displays potential anticancer activity.In the present study,we investigated the anticancer effects of celastrol against clear cell renal cell carcinoma(ccRCC) and the underlying mechanisms.Using Cancer Genome Atlas (TCGA) database and genotype-tissue expression (GTEx)database we conducted a bioinformatics analysis,which showed that the mRNA levels of liver-X receptors α (LXRα) and ATP-binding cassette transporter A1 (ABCA1) in ccRCC tissues were significantly lower than those in adjacent normal tissues.This result was confirmed by immunoblotting analysis of 4 ccRCC clinical specimens,which showed that the protein expression of LXRα and ABCA1 was downregulated.Similar results were obtained in a panel of ccRCC cell lines (786-O,A498,SN12C,and OS-RC-2).In 786-O and SN12C cells,treatment with celastrol (0.25-2.0 μM) concentration-dependently inhibited the cell proliferation,migration,and invasion as well as the epithelial-mesenchymal transition (EMT) process.Furthermore,we demonstrated that celastrol inhibited the invasion of 786-O cells through reducing lipid accumulation;celastrol concentration-dependently promoted autophagy to reduce lipid storage.Moreover,we revealed that celastrol dramatically activated LXRcα signaling,and degraded lipid droplets by inducing Iipophagy in 786-O cells.Finally,celastrol promoted cholesterol efflux from 786O cells via ABCA1.In high-fat diet-promoted ccRCC cell line 786-O xenograft model,administration of celastrol (0.25,0.5,1.0 mg·kg-1·d-1,for 4 weeks,i.p.) dose-dependently inhibited the tumor growth with upregulated LXRα and ABCA1 protein in tumor tissue.In conclusion,this study reveals that celastroi triggers lipophagy in ccRCC by activating LXRcα,promotes ABCA1-mediated cholesterol efflux,suppresses EMT progress,and ultimately inhibits cell proliferation,migration,and invasion as well as tumor growth.Thus,our study provides evidence that celastrol can be used as a lipid metabolism-based anticancer therapeutic approach.