Free Radic Biol Med. 2026 Sep 11:S0891-5849(26)01054-3. doi: 10.1016/j.freeradbiomed.2026.08.052. Online ahead of print.
ABSTRACT
7-Dehydrocholesterol (7-DHC) is the immediate precursor of cholesterol and a key intermediate in sterol biosynthesis. In addition to its established role in cholesterol and vitamin D3 metabolism, accumulating evidence indicates that 7-DHC actively regulates multiple cellular processes through its distinctive redox properties. Although abnormal 7-DHC metabolism has long been associated with human disease, the molecular mechanisms underlying its context-dependent biological effects have only recently begun to emerge. This Review summarizes the structural characteristics, biosynthesis, and metabolic regulation of 7-DHC and highlights recent advances in understanding its dual functions in physiology and pathology. Particular emphasis is placed on its roles in ferroptosis, oxidative stress, and redox homeostasis, together with their implications for Smith-Lemli-Opitz syndrome (SLOS), cancer, ischemia-reperfusion injury (IRI), atherosclerosis, and neonatal hypoxic-ischemic brain damage (HIBD). Collectively, 7-DHC emerges as a context-dependent sterol with dual biological functions, acting as either a pathological driver through toxic oxysterol formation or a protective mediator through radical-trapping and ferroptosis-suppressive activities. We further discuss the therapeutic potential of targeting 7-DHC metabolism and related signaling pathways. By integrating current mechanistic and translational evidence, this Review provides a comprehensive framework for understanding the complex biology of 7-DHC and identifies promising directions for future therapeutic development. We propose a working model in which the biological outcome of 7-DHC accumulation is determined by the balance between radical-trapping protection and oxysterol-mediated toxicity, a balance shaped by local DHCR7 activity, 7-DHC concentration and duration, membrane localization, oxidative burden, iron availability, and cellular antioxidant capacity.
PMID:42727831 | DOI:10.1016/j.freeradbiomed.2026.08.052
