3,5‐Dicaffeoylquinic Acid Delayed Aging and Promoted Oxidative Stress Tolerance via Activation of the <scp>SKN</scp> ‐1/Nrf2 Signaling Pathway

3,5-Dicaffeoylquinic acid (3,5-diCQA), as a plant-derived polyphenol, exhibits multiple bioactivities, including anti-inflammation, antioxidation, and anti-diabetes. A previous report demonstrated that 3,5-diCQA increased the lifespan and promoted the healthspan in <i>Caenorhabditis elegans</i>. Nevertheless, the molecular mechanisms underlying the function of 3,5-diCQA remain to be further determined. In this study, 3,5-diCQA promoted the transfer of SKN-1 to nucleus and upregulated the expressions of its downstream genes. Moreover, 3,5-diCQA enhanced oxidative stress tolerance and decreased ROS level in a <i>skn-1</i>-dependent manner. Consistently, 3,5-diCQA remarkably reduced the ROS level and delayed senescence of MRC-5 cells by activating Nrf2. Notably, molecular docking results revealed that 3,5-diCQA was found to occupy the binding pocket of Keap 1 (Kelch-like epichlorohydrin-associated protein 1), a cytoplasmic repressor of Nrf2, thereby promoting Nrf2 activation. Overall, this study demonstrated that SKN-1/Nrf2 signaling is essential for 3,5-diCQA to exert its anti-aging and stress resistance-enhancing effects. Our findings elucidate novel mechanisms by which 3,5-diCQA activates the SKN-1/Nrf2 pathway, highlighting its promise as candidate for delaying aging and attenuating oxidative stress-related disorders.