Zinc ions facilitate metabolic bioenergetic recovery post spinal cord injury by activating microglial mitophagy through the STAT3-FOXO3a-SOD2 pathway.

Spinal cord injury (SCI) is a devastating condition of the central nervous system (CNS) with high global rates of disability and mortality, and no effective cure currently available. Microglia play a critical role in the progression of SCI, and enhancing their metabolic function may facilitate tissue repair and recovery. Mitochondrial dysfunction is a key feature of metabolic impairment, with the regulation of autophagy being essential for maintaining mitochondrial homeostasis and cell survival. The transcription factor Forkhead box O3a (FOXO3a) is integral to cellular metabolism, mitochondrial dysfunction, and oxidative stress responses, yet its role in post-SCI microglial metabolism remains underexplored. In this study, single-cell RNA sequencing reveals the crucial involvement of the FOXO signaling pathway in zinc ion-mediated enhancement of microglial metabolism. Mechanistically, oxidative stress-induced reactive oxygen species (ROS) accumulation exacerbates metabolic dysfunction by promoting excessive mitochondrial fission and impairing mitophagy. Importantly, zinc ions induce the nuclear translocation of FOXO3a, leading to its activation as a transcription factor. This activation enhances mitochondrial autophagy and fusion processes, thereby restoring microglial metabolic capacity. Our findings suggest that the zinc ion regulation of the STAT3-FOXO3a-SOD2 axis is pivotal in modulating mitochondrial gene expression, which governs microglial energy homeostasis and improves the spinal cord microenvironment, potentially enhancing neuronal survival. These insights highlight a promising therapeutic target for SCI.