Abstract

BACKGROUND The reliance of clear cell renal cell carcinoma (ccRCC) on exogenous cholesterol import implies a metabolic susceptibility. This susceptibility represents a potential avenue that can be exploited as a novel therapeutic approach for ccRCC. Circular RNAs (circRNAs) are emerging regulators in cancer, yet their roles in ccRCC lipid metabolism and tumor microenvironment remodeling remain unclear. This study investigates the tumor-promoting role of circABCA1 in ccRCC cholesterol homeostasis and M2 macrophage polarization. METHODS The expression levels of circABCA1, IGF2BP3, SCARB1, autophagy-related proteins, and the IGF1R/PI3K/AKT/mTOR and ABCA1/ABCG1 pathways were measured using RT-qPCR and western blot. Untargeted metabolomics, RNA- sequencing, and MS2 RNA-pulldown were conducted to identify targets. Interaction analyses included RNA immunoprecipitation, RNA pull-down, and RNA fluorescence in situ hybridization (FISH) assays. Lipid raft measurements, cholesterol uptake/efflux assays, and lipophagy assessments were performed. A co-culture system between M2 macrophages and ccRCC cells was established. In vivo tumorigenesis and metastasis were evaluated using xenograft models and a hepatic metastasis model. Statistical analyses involved Student's t-tests and ANOVA; significance set at P?