Kaempferol Attenuates Spaceflight-associated Knee Cartilage Degeneration by Targeting NOX4-Mediated Mitochondrial Dysfunction

Microgravity and space radiation experienced during spaceflight have negative effects on musculoskeletal health, yet their impact on articular cartilage remains poorly understood. In this study, we demonstrated that simulated spaceflight on Earth leads to cartilage degeneration in the knees of mice. Similar changes were also observed in mice exposed to actual space flight. To investigate the mechanisms behind spaceflight-associated cartilage loss, human chondrocytes were encapsulated within a hydrogel scaffold and then subjected to rotary culture to mimic the alterations caused by microgravity. Simulated microgravity increased the expression of biomarkers related to inflammation and cellular senescence. Additionally, rotary culture decreased mitochondrial respiration and increased the production of reactive oxygen species. Through RNA sequencing and bioenergetic profiling, we identified NADPH oxidase 4 (NOX4) as a crucial factor driving these changes. Additionally, kaempferol, a naturally occurring flavonoid that directly binds to NOX4, was found to partially reverse the harmful effects of microgravity on chondrocytes. Finally, systemic administration of kaempferol reduced cartilage degradation in mice subjected to simulated spaceflight on the ground. These findings establish that NOX4-mediated mitochondrial dysfunction is a key mechanism underlying spaceflight-induced cartilage degeneration and highlight kaempferol as a potential protective measure for joint health in space.