This comprehensive study sheds new light on how space conditions specifically impact kidney health during prolonged missions. Researchers combined data from 40 space mission samples, including human astronauts and animal models from the International Space Station and laboratory simulations of deep space radiation. One of the most striking findings is that the kidney tubules responsible for regulating calcium and salt balance undergo remodeling and shrinkage within less than a month in space. This structural change is primarily attributed to microgravity rather than galactic cosmic radiation (GCR), though the interaction between these factors may exacerbate damage. Previously, kidney stones in astronauts were assumed to form mainly due to bone density loss-induced calcium buildup in urine. However, this study reveals that altered salt processing by the kidneys in space likely plays a key role in stone formation. This insight could lead to new preventive measures. Most concerning is the permanent kidney damage found in mice exposed to simulated GCR doses equivalent to a 2.5-year Mars mission, implying serious health risks for astronauts on extended journeys beyond Earth’s magnetic protection. The study emphasizes that current radiation shielding cannot fully protect astronauts’ kidneys from galactic radiation, highlighting the urgent need for developing pharmaceutical or technological interventions. Such measures might also benefit patients on Earth, such as those receiving radiotherapy for cancer by protecting their kidney function. Overall, this research expands our understanding of spaceflight’s hidden biological risks and paves the way for tailored kidney protection strategies, critical for the future of human exploration to Mars and beyond.