Isoquercetin alleviates osteoarthritis via regulating the NOX4/Nrf2 redox imbalance in senescent chondrocytes

The redox imbalance induced by excessive Reactive Oxygen Species (ROS) contributes to senescent phenotypes of chondrocytes in osteoarthritis (OA). However, there is limited evidence regarding the involvement of NADPH oxidase-4 (NOX4)/NFE2-related factor 2 (Nrf2) redox imbalance in OA. Isoquercetin (IQ), a quercetin derivative, exhibits promising antioxidative and Anti-aging properties. Here, we found that IQ promoted redox homeostasis by inhibiting NOX4 and activating Nrf2-mediated antioxidant responses, thereby ameliorating OA. Specifically, IQ significantly suppressed the expression of senescence-associated secretory phenotypes (SASPs) in senescent chondrocytes. RNA Sequencing analysis revealed that cellular senescence and oxidative stress were involved in the mechanism of IQ's effect on senescent chondrocytes. IQ effectively reversed redox imbalance, as evidenced by reduced levels of ROS and endogenous oxidants, and increased mitochondrial membrane potential and, elevated levels of endogenous Antioxidants. Mechanistically, the elevated expression of NOX4 observed in patients with severe OA confirms its role in OA pathogenesis. Molecular docking and NOX4 knockdown experiments suggested that IQ may interact with NOX4 and inhibit its expression. This study identifies a potential therapeutic target and provides a promising candidate for OA treatment.

Cellular senescence; Isoquercetin; NADPH oxidase 4; Osteoarthritis; Oxidative stress.