Skin-derived volatile organic compounds trigger redox signalling pathways in human keratinocytes via gas-phase interaction.

Human skin emits a diverse range of volatile organic compounds (VOCs) originating from both endogenous metabolic activity and microbial transformation of sweat and sebum. While these volatiles have been profiled extensively, their potential to influence host cellular processes remains largely unexplored. In this study, we investigate the capacity of five skin-relevant VOCs-nonanal, decanal, 6-methyl-5-hepten-2-one (6MHO), acetic acid (AA), and 2-ethyl-1-hexanol (2EH) - to induce redox signalling pathways in keratinocytes. We demonstrate that selected compounds, particularly nonanal, decanal and AA, induce intracellular reactive oxygen species (ROS) and activate the Nrf2-Keap1 antioxidant defence mechanism. Using both conventional liquid-phase treatment and a custom-designed headspace system for gas-phase treatment, we show that these VOCs elicit this signalling response from both liquid and gas phases. These findings provide the first mechanistic evidence that endogenous or microbially-derived VOCs from skin can function as gaseous redox modulators, capable of triggering protective cellular responses from a distance. This work presents new evidence for cell-cell volatile communication in skin and through its resident microbiota, offering insights into the signalling potential of volatile metabolites.