Glis1 regulates metabolic programming by promoting H3K18 lactylation to alleviate neuronal senescence following spinal cord injury.

Neuronal senescence is a significant factor impeding spinal cord injury (SCI) repair. Research indicates that Glis1, a Kruppel-like zinc finger transcription factor, is pivotal in reprogramming senescent cells and enhancing genomic stability via lactylation. Histone lactylation, an epigenetic modification using lactate as a substrate, becomes prominent post-SCI due to increased neuronal lactate levels. However, the mechanisms linking neuronal senescence and histone lactylation following SCI remain poorly understood. This study elucidates the roles of Glis1, H3K18 lactylation, and neuronal senescence through comprehensive in vivo and in vitro investigations. The findings reveal a post-SCI rise in neuronal lactate levels, accompanied by cellular senescence. Furthermore, upregulation of Glis1 attenuates senescence and promotes histone lactylation. The downstream target secretogranin II (SCG2), identified via ChIP-seq and RNA-seq, was found to exert negative feedback on glycolytic metabolism and lactylation, thereby suppressing neuronal senescence. These results unveil a novel regulatory mechanism of Glis1 in neuronal senescence following SCI through the p300/H3K18la/SCG2 axis, offering a new therapeutic target for spinal cord repair.