Mass spectrometry analysis of eight astronauts' blood samples revealed significant alterations in 16 plasma proteins during six-month International Space Station missions. The affected proteins span four critical pathways: immune function, cellular structure maintenance, blood clotting, and metabolic regulation. Notable changes included disrupted levels of APOL1, ITIH2, PLEK, GP1BA, BASP1, and IGFBP4. This proteomic profiling represents a significant advance in understanding space medicine at the molecular level. Previous research has documented astronauts' bone loss, muscle atrophy, and cardiovascular changes, but comprehensive protein-level analysis has been limited. The findings suggest space travel triggers systematic cellular stress responses that persist even after returning to Earth's gravity. For emerging space tourism and long-duration missions, these protein signatures could serve as biomarkers for health monitoring and intervention strategies. The study's limitation lies in its small cohort size and inability to establish causation versus correlation. However, the identification of specific protein targets opens pathways for developing countermeasures against space-induced physiological changes. As commercial spaceflight expands, understanding these molecular adaptations becomes increasingly relevant for protecting both professional astronauts and civilian space travelers from the health consequences of microgravity exposure.