5,6-epoxycholestanols metabolism and functions: Defining the epoxycholestanoid (EChA) family

The oxidation of cholesterol at the Δ⁵ double bond generates 5,6-epoxycholestanols (5,6-ECs), which exist as two diastereoisomers, 5,6α-EC and 5,6β-EC. These metabolites define a distinct branch of sterol metabolism that integrates redox chemistry with receptor signaling. Once considered artefactual autoxidation products, 5,6-ECs are now recognized as regulated intermediates arising from enzymatic, oxidative, and environmental sources, and yielding structurally and functionally diverse metabolites, here termed the epoxycholestanoid (EChA) family. Cholesterol-5,6-epoxide hydrolase (ChEH; EBP/DHCR7 complex) converts 5,6-ECs into cholestane-3β,5α,6β-triol (CT), which is subsequently oxidized by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) to form 6-oxocholestan-3β,5α-diol (OCDO), a glucocorticoid receptor (GR)-biased agonist that promotes tumor growth. In parallel, 5,6α-EC undergoes stereoselective conjugation with histamine to generate dendrogenin A (DDA), an endogenous liver X receptor β (LXRβ)-biased agonist that displays tumor suppressive and neurostimulating functions. These opposing OCDO-GR and DDA-LXRβ pathways are embedded in enzyme-coupled feedback loops that link oxidative stress, sterol metabolism, and transcriptional control. This review integrates lipidomics, enzymology, receptor pharmacology, and disease biology to define the EChA family as a conserved redox-responsive signaling network at the interface of cholesterol metabolism, inflammation, ageing, and disease, offering new opportunities for biomarker discovery and therapeutic intervention.