Exploring roles of neuroglobin in oxygen homeostasis and neurodevelopment based on human cerebral organoid models.

Neuroglobin (NGB) is a neuron-enriched globin known for its neuroprotective role under hypoxic and oxidative stress conditions. However, its function in neurodevelopment remains largely unexplored. Using human cerebral organoids (hCOs), we investigate the impact of NGB silencing on oxygen homeostasis, neurogenesis, and cortical organization. The experimental results demonstrate that NGB regulates intra-organoid oxygen tension, supporting neuronal differentiation, and cortical maturation. Silencing NGB disrupts this process, leading to sustained hypoxia, impaired synaptic connectivity, and activation of stress-response pathways, including DNA damage response (DDR), unfolded protein response (UPR), and mTORC1 signaling. Persistent oxidative stress and metabolic reprogramming further drive neural progenitor cells toward senescence, impairing neurogenic trajectories. These cellular and structural abnormalities in NGB-silenced hCOs are similar to pathological features of neurodegenerative diseases. Our study highlights critical roles of NGB in oxygen-dependent neurodevelopmental processes and suggests that targeting cellular senescence and oxidative stress may offer therapeutic strategies for neurodevelopmental and neurodegenerative disorders.