The oxysterolome iterative metabolism expands sterol signaling.

Oxysterols are generally viewed as individual signaling molecules regulating lipid homeostasis, immunity, development, and disease. However, many primary oxysterols are metabolic hubs that undergo iterative enzymatic transformations, generating secondary and higher-order metabolites with distinct biological activities. We propose the oxysterolome to describe this interconnected network of oxygenated sterols and their metabolic descendants. Through receptor diversification, functional divergence, and the emergence of novel biological activities, iterative metabolism expands the informational and functional diversity of cholesterol-derived signaling. Deciphering the oxysterolome will require moving from the study of individual metabolites toward reconstruction of interconnected metabolic networks, providing new perspectives for understanding endocrine regulation, aging, immunity, and disease.