Oxysterols (OHCs)

Oxysterols are a diverse class of 27-carbon oxygenated derivatives of cholesterol that serve as crucial bioactive lipids and signaling molecules in human physiology [2, 11]. They are produced through enzymatic oxidation via cytochrome P450 enzymes—such as sterol 27-hydroxylase (CYP27A1) and cholesterol 24-hydroxylase (CYP46A1)—or non-enzymatically through reactive oxygen species [2, 4]. Biologically, oxysterols function as endogenous ligands for various receptors, including the Liver X Receptors (LXRα and LXRβ), Retinoic acid-related Orphan Receptors (RORs), and the G-protein coupled receptor EBI2 (GPR183), thereby regulating lipid metabolism, immune cell migration, and inflammatory responses [1, 7, 13]. Pathologically, they are implicated in the progression of atherosclerosis, neurodegenerative diseases like Alzheimer's, and certain cancers, where they can act as selective estrogen receptor modulators (SERMs) or pro-inflammatory mediators [6, 9, 11]. Therapeutic strategies involving oxysterols focus on modulating their biosynthetic enzymes or targeting their receptors; for instance, semi-synthetic oxysterol analogues like Oxy133 and Oxy210 are under development for bone regeneration and anti-inflammatory applications, respectively [3, 15, 23]. However, drug development in this area faces challenges such as the potential for off-target LXR activation leading to hepatic steatosis and the complex, often opposing biological effects of different oxysterol species [18, 19].

Other names

Cholesterol oxidation productsCOPsHydroxycholesterolsOxidized cholesterolOHCs

As bioactive ligands, oxysterols modulate cellular physiology through the activation or inhibition of nuclear receptors such as Liver X Receptors (LXR) and Retinoic acid-related Orphan Receptors (ROR), as well as G-protein coupled receptors like EBI2 [1, 7, 13]. They also serve as precursors to bile acids and play a critical role in the feedback inhibition of cholesterol biosynthesis by promoting the degradation of HMG-CoA reductase and regulating SREBP maturation via interaction with Insig proteins [16, 21, 22].