Natural monoterpenoid geraniol promotes antioxidant defense and stress tolerance via SKN-1/Nrf2 activation in Caenorhabditis elegans

Abstract

Oxidative stress (OS) is a major contributor to aging and the pathogenesis of numerous conditions, including dia- betes, neurodegenerative, cardiovascular, and autoimmune disorders. Consequently, therapeutic strategies aimed at enhancing endogenous cytoprotective pathways have gained significant interest. Plant-derived essential oils rep- resent attractive sources for such interventions due to their natural origin and low toxicity; specifically, the monoter- penoid geraniol, a principal component of rose oil, has demonstrated promising antioxidant properties in vitro. In this study, we utilized Caenorhabditis elegans to investigate the in vivo efficacy and molecular mechanisms of geraniol effect. Our results show that geraniol significantly reduces intracellular reactive oxygen species and enhances resist- ance to acute OS induced by juglone. Mechanistic characterization using GFP-reporter strains revealed that geraniol activates the DAF-16/FOXO and SKN-1/Nrf2 transcription factors, while surprisingly causing a slight but consistent downregulation of the HSF-1-mediated heat-shock response. Crucially, genetic epistasis analysis using null/hypomor- phic mutants demonstrated that only SKN-1 is strictly essential for geraniol-mediated protection against induced OS. In conclusion, this study underscores the utility of C. elegans as a robust and accessible platform for the pharmacologi- cal screening of natural products. Our findings establish geraniol, a key constituent of rose oil, as a multifunctional modulator of cellular defenses that orchestrates multiple cytoprotective pathways, identifying the SKN-1-dependent response as a critical driver of its antioxidant efficacy in C. elegans. By delineating this specific genetic requirement, these results provide a mechanistic foundation that supports the therapeutic potential of geraniol in mitigating aging and pathophysiology driven by OS