Oxysterols in the defense against viral infections in humans

Oxysterols, a diverse class of cholesterol oxidation products, are increasingly recognized as important modulators of innate antiviral defense. Among them, the enzymatically derived molecules 25-hydroxycholesterol (25OHC) and 27-hydroxycholesterol (27OHC; chemically 25R,26-hydroxycholesterol) exhibit broad and potent antiviral activity across numerous human viral pathogens. Produced by the interferon-inducible enzyme cholesterol 25-hydroxylase (CH25H) and the mitochondrial enzyme CYP27A1, these oxysterols are present in human biological fluids at physiologically relevant concentrations, suggesting an evolutionarily conserved protective function. Over the past decade, extensive in vitro, ex vivo, and in vivo studies have confirmed their ability to inhibit both enveloped and non-enveloped viruses through host-directed mechanisms that include modulation of cholesterol synthesis and trafficking, disruption of viral entry and membrane fusion, alteration of endocytic pathways, interference with viral genome replication, and activation of antiviral immune signaling. Because these molecules target host pathways rather than viral components, they show a markedly reduced propensity to select resistant viral variants and often retain efficacy even when administered post-infection. Synthetic oxysterol analogs further highlight the therapeutic potential of modulating oxysterol-regulated pathways. Collectively, current evidence positions natural and synthetic oxysterols as promising candidates for the development of broad-spectrum, host-directed antiviral strategies applicable to both emerging and established viral infections.