SGK1 inhibition supports neuroprotection in spinal cord injury by suppressing oxidative stress and AIM2 activation via FoxO1 mediated mitophagy

Spinal cord injury (SCI) is accompanied by a significant microglia-associated inflammatory response that is associated with secondary tissue damage and poorer functional outcomes. Serum and glucocorticoid-regulated kinase 1 (SGK1) has been implicated in the regulation of cell survival and neuronal excitability in various diseases. However, the role and cell-specific mechanism of SGK1 in SCI remain to be elucidated. In this study, we observed that SGK1 was predominantly expressed in microglia located at the lesion margin during the early phase of SCI in a mouse contusion model. Inhibition of SGK1 by GSK650394 has been shown to promote neural repair while simultaneously suppressing neuroinflammation and mitochondrial oxidative stress. Mechanistically, the inhibition of SGK1 results in a reduction of FoxO1 phosphorylation and the promotion of nuclear import, consequently inducing microglial mitophagy and promoting mitochondrial homeostasis, leading to the suppression of absent in melanoma 2 (AIM2) related pyroptosis and the conversion of microglia into a neuroprotective M2 phenotype. In particular, AIM2 overexpression or deletion effectively interfered with the influence of SGK1-FoxO1 on the modulation of SCI. In conclusion, the present findings provide a potential therapeutic strategy for the treatment of SCI.