Our findings suggest that PBX3 could regulate tumor cell cholesterol biosynthesis by regulating the transcriptional activity of HMGCR, thereby unraveling a novel regulatory pathway of cholesterol metabolism in tumor cells. Notably, while further investigations are needed, PBX3 might also affect the expression of other lipid metabolism-related genes, such as FASN, SBCAD, and PECR, although less significant than its effect on HMGCR. Here, PECR is linked to neoplasm.