Kaempferol Attenuates Spaceflight-Associated Knee Cartilage Degradation by Targeting NOX4-Mediated Mitochondrial...

Microgravity and space radiation experienced during spaceflight have adverse effects on musculoskeletal health, yet their impact on articular cartilage has not been fully understood. In this study, we demonstrated that simulated spaceflight on Earth leads to cartilage degradation in the knees of mice. Similar changes were also observed in mice exposed to actual spaceflight. To investigate mechanisms underlying spaceflight-associated cartilage loss, human chondrocytes were encapsulated in a hydrogel scaffold and subjected to rotary culture to simulate microgravity-induced alterations. Simulated microgravity increased the expression of biomarkers related to inflammation and cellular senescence. Additionally, rotary culture decreased mitochondrial respiration and increased reactive oxygen species production. Through RNA sequencing and bioenergetic profiling, we identified NADPH oxidase 4 (NOX4) as a crucial factor driving these changes. Moreover, 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 degradation and highlight kaempferol as a potential protective measure for joint health in space.