Actl6a Regulates Autophagy via Sox2-Dependent Atg5 and Atg7 Expression to Inhibit Apoptosis in Spinal Cord Injury

Spinal cord injury (SCI) is a severe central nervous system disorder, and effective treatments for its repair remain elusive. The molecular mechanisms driving both injury and regeneration are not yet fully understood. In this study, we explore the role of Actin-like protein 6A (Actl6a) in neuronal survival and SCI repair, with a focus on its regulation of autophagy and apoptosis through its interaction with the transcription factor Sox2. Our results reveal that Actl6a expression is significantly reduced following SCI, which contributes to elevated levels of apoptosis. Overexpression of Actl6a inhibits apoptosis by promoting autophagy, resulting in improved functional recovery both in vitro and in vivo, underscoring its potential as a therapeutic target. Mechanistically, Actl6a enhances the expression of the key autophagy-related genes Atg5 and Atg7 through direct interaction with Sox2 at their promoter regions. This regulatory mechanism is further modulated by Fto, which alters the m6A methylation status of Actl6a mRNA, thereby influencing its stability and gene expression. These findings emphasize the pivotal role of the Fto/Actl6a/Sox2 axis in modulating autophagy and apoptosis in SCI, offering promising insights for therapeutic strategies aimed at SCI repair.