2-Methoxystypandrone from Polygonum cuspidatum Rejuvenates Senescence by Reducing Mitochondrial ROS

Oxidative stress induced by reactive oxygen species (ROS) is a major contributor to senescence. Although strategies to mitigate ROS are considered crucial for reversing this process, effective interventions remain limited. Extracts from <i>Polygonum cuspidatum</i> (<i>P. cuspidatum</i>) have shown protective effects against senescence by suppressing mitochondrial ROS production; however, the specific bioactive compound responsible for these effects has not yet been identified. This study aimed to identify the active compound in <i>P. cuspidatum</i> responsible for reducing mitochondrial ROS and to elucidate its mechanism of action in rejuvenating senescence. Bioactive components of <i>P. cuspidatum</i> extract were screened for their ability to decrease mitochondrial ROS production. The most potent compound, 2-methoxystypandrone (2-MS), was further examined for its effects on oxidative phosphorylation (OXPHOS) efficiency, mitochondrial ROS generation, and senescence-associated phenotypes in a skin cell-based model. 2-MS was identified as the most effective compound for reducing mitochondrial ROS. Mechanistically, 2-MS enhanced OXPHOS efficiency, thereby minimizing ROS production resulting from inefficient respiration. Reduction in mitochondrial ROS by 2-MS restored senescence-associated phenotypes and rejuvenated senescence by suppressing ROS-driven melanogenesis and inflammatory responses in skin cells. This study identifies 2-MS as a key active ingredient of <i>P. cuspidatum</i> that exerts anti-aging effects through the reduction in mitochondrial ROS generation. These findings highlight 2-MS as a promising therapeutic and cosmetic candidate for rejuvenating senescence.