Space flight enhances stress pathways in human neural stem cells (NSCs). This study investigated the effects of microgravity on NSCs, focusing on their behavior after readapting to Earth's gravity. NSCs exposed to space flight showed increased survival and self-renewal, but some exhibited enhanced stress responses and autophagy-like behavior (ALB). The secretome from space-flown NSCs was found to induce ALB in naive NSCs, with SPARC being the most abundant protein in the secretome. SPARC is involved in extracellular matrix synthesis and can induce endoplasmic reticulum (ER) stress, leading to cell death. The study suggests that SPARC may act as a microgravity sensor, and its expression is upregulated by space microgravity. These findings highlight the potential of SPARC as a biomarker for microgravity-induced stress and provide insights into the mechanisms underlying NSC responses to space conditions. The results also indicate that space flight may contribute to intracranial hypertension in astronauts. The study underscores the importance of understanding gravity-sensing molecules to develop effective countermeasures for long-duration space missions.Space flight enhances stress pathways in human neural stem cells (NSCs). This study investigated the effects of microgravity on NSCs, focusing on their behavior after readapting to Earth's gravity. NSCs exposed to space flight showed increased survival and self-renewal, but some exhibited enhanced stress responses and autophagy-like behavior (ALB). The secretome from space-flown NSCs was found to induce ALB in naive NSCs, with SPARC being the most abundant protein in the secretome. SPARC is involved in extracellular matrix synthesis and can induce endoplasmic reticulum (ER) stress, leading to cell death. The study suggests that SPARC may act as a microgravity sensor, and its expression is upregulated by space microgravity. These findings highlight the potential of SPARC as a biomarker for microgravity-induced stress and provide insights into the mechanisms underlying NSC responses to space conditions. The results also indicate that space flight may contribute to intracranial hypertension in astronauts. The study underscores the importance of understanding gravity-sensing molecules to develop effective countermeasures for long-duration space missions.