Oxysterols at the Crossroads of Cholesterol Metabolism and Cancer

Oxysterols are oxygenated derivatives of cholesterol. They emerge as central mediators linking lipid metabolic rewiring to oncogenic signaling and redox imbalance. Among them, a distinct metabolic module centered on 5,6-epoxides of cholesterol (5,6-EC) defines a critical branching point between tumor-suppressive and tumor-promoting lipid pathways. This review highlights recent findings identifying the 5,6-EC/OCDO/DDA/27OH-OCDO axis as a metabolic switch that integrates cholesterol oxidation with cancer cell fate. In healthy tissues, the stereoselective conjugation of 5,6α-epoxycholesterol with histamine yields dendrogenin A (DDA), an endogenous, LXRβ-biased agonist that restores differentiation, maintains redox homeostasis, and promotes an antitumor immune activation. During carcinogenesis, up-regulation of cholesterol-5,6-epoxide hydrolase (ChEH) together with ectopic expression of 11β-HSD2 redirects the same intermediates toward oncosterone (OCDO), an oncometabolite that fuels proliferation, migration in a GR-dependent manner, and induce a immune suppression. This metabolic inversion, loss of DDA and emergence of OCDO, marks a characteristic lipid metabolic deregulation in breast cancer. Counterbalancing this oncogenic flux, CYP27A1 converts OCDO into 27-hydroxy-OCDO (27OH-OCDO), an antiproliferative oxysterol showing that CYP27A1 functions as a metabolic checkpoint restoring proliferative control. Together, these findings reveal how cholesterol oxidation, redox balance, and receptor signaling converge through a single sterol pathway to determine tumor progression or suppression. Understanding and manipulating this axis opens new therapeutic and chemopreventive opportunities within the landscape of lipid metabolic alterations in cancer.