Leveraging integrated multiomics data from NASA’s Inspiration4, Polaris Dawn, and Ax-2 space missions, researchers defined molecular signatures associated with human physiological adaptation to spaceflight. Comprehensive analyses—including proteomics, epigenomics, single-cell transcriptomics, and CRISPR knockout screens—revealed consistent changes in stress response, immune signaling, mitochondrial function, DNA repair, and hematopoiesis. These findings provide temporal and mechanistic insights critical for enhancing astronaut health monitoring and developing targeted countermeasures for long-duration lunar and interplanetary missions.