Year: 2025
Type: preprint
Abstract: 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.
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4415524965
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