A ferroptosis-related transcriptional signature in the brain after a 35-day spaceflight

As long-term human spaceflight becomes increasingly feasible, understanding the biological effects of the space environment on the human body has become ever more important. Among the environmental factors that distinguish space from Earth, microgravity and space radiation have been reported to exert diverse effects on the central nervous system, including signs of accelerated aging, structural alterations of the brain, and cognitive impairment. Because the brain is a highly complex organ with region-specific functions and metabolic characteristics, it is essential to investigate brain region–specific responses to spaceflight. Open Science Datasets provided by NASA GeneLab (OSD-682, 685, 698, and 699) provide transcriptomic profiles from four anatomically distinct brain regions following 35 days of spaceflight, with and without antioxidant treatment. Previous studies and related datasets have demonstrated that spaceflight induces oxidative stress and mitochondrial damage in the brain. Although such conditions are compatible with molecular features associated with ferroptosis, an iron-dependent form of programmed cell death described relatively recently, the relationship between spaceflight and ferroptosis in the brain has not yet been systematically examined. In this study, we analyzed region-resolved transcriptomic profiles to show at the pathway level that long-term spaceflight is associated with selective ferroptosis-related transcriptional signatures in the hippocampus, particularly within the dentate gyrus. We further suggest that iron dysregulation and increased reactive oxygen species may contribute to these transcriptional alterations. In addition, the observed association between ferroptosis-related pathways and the enrichment of neurodegenerative disease–related pathways in the dentate gyrus supports the notion that ferroptosis may represent a potential molecular mechanism contributing to spaceflight-induced neurodegenerative alterations.