The Natural Flavonoid Isoscoparin Ameliorates Oxidative Stress and Mitochondrial Dysfunction in <i>C. elegans</i> and Macrophages

The natural flavonoid isoscoparin exhibits potent antioxidant activity, but its protective mechanisms against oxidative stress and mitochondrial dysfunction remain incompletely understood. This study investigated the effects of isoscoparin in Caenorhabditis elegans and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. In C. elegans, isoscoparin significantly reduced intracellular reactive oxygen species (ROS) levels and enhanced resistance to paraquat-induced oxidative stress. These effects were associated with upregulation of antioxidant genes (daf-16, skn-1, sod-3, gst-4, ctl-1, ctl-2). In macrophages, isoscoparin not only enhanced the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) content but also attenuated LPS-induced mitochondrial ROS generation. Furthermore, isoscoparin restored mitochondrial respiratory function by improving basal and maximal respiration, ATP production, and spare respiratory capacity. It also stabilized mitochondrial membrane potential and restored the expression of electron transport chain complexes I-V. These findings demonstrate that isoscoparin alleviates oxidative stress through dual mechanisms: enhancing antioxidant defense via conserved pathways and directly protecting mitochondrial integrity. This study highlights the potential of isoscoparin as a therapeutic candidate for oxidative stress-related diseases.