Monoammonium glycyrrhizinate ameliorates mitochondrial dysfunction-mediated oxidative stress and neuroinflammation via the NRF2/NQO1 axis after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI)-induced mitochondrial dysfunction in microglia exacerbates neuroinflammation and neurological deficits. Monoammonium glycyrrhizinate (MAG), a bioactive liquorice-derived compound, exhibits anti-inflammatory and antioxidant properties; however, its effects on microglial mitochondria remain unknown. METHODS: Mice received a moderate contusion injury at the T10 spinal segment. Histopathology was assessed using Hematoxylin-Eosin, Nissl staining, and Luxol Fast Blue; locomotor recovery was evaluated via the Basso Mouse Scale, hindlimb flexion scoring, and gait footprint analysis. RNA-Seq and molecular docking identified KEAP1/NRF2 signaling. Verification employed qPCR, Western blot, and immunofluorescence. Mitochondrial function was gauged by JC-1 and MitoSOX. RESULTS: In SCI mice, MAG attenuated neuroinflammation, reduced neuronal tissue loss and demyelination, enhanced neuronal survival, and improved functional recovery. Transcriptomic and molecular docking established that MAG directly activates NRF2, promoting dissociation from KEAP1, nuclear translocation, and induction of NQO1. Pathway enrichment analysis further indicated MAG modulation of mitochondrial regulatory processes. MAG treatment significantly restored mitochondrial function in BV2 cells, improving membrane potential and reducing oxidative stress. Critically, NRF2 inhibition with ML385 abolished MAG's protective effects on anti-inflammatory responses and antioxidant activity. CONCLUSION: This study identifies MAG as a novel activator of the KEAP1/NRF2/NQO1 axis, alleviating microglial mitochondrial dysfunction and neuroinflammation post-SCI. These findings provide mechanistic insights into MAG's neuroprotective actions and support its therapeutic potential.