Sex‐Specific Changes in Brain Organoids from Acute Simulated Galactic Cosmic Radiation are Rescued by Targeted ECM Pathway Stimulation

Abstract As deep‐space missions become increasingly feasible, understanding the health risks posed by galactic cosmic rays (GCR) is critical. This study investigates the effects of a simplified 5‐ion GCR simulation (simGCRsim) on human brain organoids derived from 12 human induced pluripotent stem cell (hiPSC) lines. Male organoids exhibit increased vulnerability, characterized by reduced SOX2‐positive neural progenitor populations, downregulation of outer kinetochore genes including components of the NDC80 complex, centromere loss, and elevated nuclear p53 accumulation. Female organoids also exhibit radiation‐induced neuronal damage but show comparatively lower levels of centromere disruption and p53 activation than males. To counteract these effects, an optogenetically controlled FGF2 signaling system is applied, leveraging plant‐derived light‐sensitive domains. Activation of this system enhances extracellular matrix (ECM) expression, resulting in significant neuroprotection against simGCRsim‐induced damage. Furthermore, exogenous ECM supplementation alone effectively mitigated radiation‐induced neural injury in both male and female brain organoids. These findings highlight the central role of ECM in neuroprotection under cosmic radiation exposure and suggest a potential strategy for safeguarding astronaut brain health during long‐duration spaceflight.