{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeuroglobin (NGB) is a highly conserved, neuron‐expressed globin distinguished by its unusual heme hexacoordination. Structural and spectroscopic studies have revealed that in both its ferric and ferrous states the heme iron is coordinated by proximal and distal histidine residues—a configuration that is dynamically modulated by redox‐sensitive disulfide bond formation and alterations in the distal heme pocket. These features enable NGB to reversibly bind oxygen and to potentially facilitate oxygen release under hypoxic conditions, suggesting a role in oxygen sensing and storage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond oxygen binding, NGB functions as a redox sensor whose ligand reactivity is regulated by post‐translational modifications. Changes in its redox state—via disulfide bond rearrangement, phosphorylation, and consequent shifts from a six‐ to a five–coordinated heme—promote nitrite binding and reduction. This nitrite reductase activity enables the generation of nitric oxide (NO), thereby linking NGB to NO‐dependent signaling pathways that can modulate cellular responses to hypoxia and oxidative stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn models of cellular stress, NGB exerts potent neuroprotective and anti‐apoptotic effects. Under hypoxic or oxidative conditions, its expression is upregulated and NGB is re‐distributed to mitochondria where it can interact with cytochrome c, thereby inhibiting the intrinsic apoptotic cascade (for example, by preventing pro‐caspase 9 activation). In addition, NGB acts as a guanine nucleotide dissociation inhibitor (GDI) for heterotrimeric G proteins, contributing to the modulation of second messenger systems that bolster cell survival. These actions, observed in both in vitro neuronal models and clinical correlations with reduced brain injury, underscore a critical role for NGB in cellular stress adaptation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, diverse stimuli—including hemin, estrogen, and hypoxic/ischemic stress—modulate NGB expression and localization, broadening its functional scope to include roles in energy metabolism, autophagy, axon regeneration, and cellular detoxification. Upregulation of NGB has been reported in conditions ranging from stroke and traumatic brain injury to certain cancers and even within sensory tissues like the retina and cochlea. Engineered NGB derivatives—including cell‐penetrating and ligand–scavenging variants—have been developed to enhance its protective capacity, for example by sequestering carbon monoxide or hydrogen sulfide, thereby opening promising therapeutic avenues for neurodegenerative disorders, ischemia, and oxidative injuries."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chenggang Zhang, Chunli Wang, Meiyu Deng, et al. 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