A peptide drug targeting SASH1-PKM2 interaction promotes recovery of traumatic brain injury in mice.

Traumatic brain injury (TBI) has the highest incidence rate and remains a major therapeutic challenge. After TBI, astrocytes are rapidly activated, with these reactive astrocytes contributing to glial scar formation, which hinders neural regeneration. Thus, strategies that limit astrocyte activation can promote functional recovery post-TBI. SASH1, a multifunctional scaffold protein, is primarily expressed in astrocytes and regulates their maturation and activation, as demonstrated in our previous study. This study aims to determine whether inhibiting SASH1 function aids in TBI repair and to explore the underlying molecular mechanisms. Our data demonstrate that SASH1 interacts with PKM2, and silencing SASH1 in astrocytes leads to increased nuclear accumulation of PKM2. Additionally, in SASH1-deficient astrocytes, glucose uptake and lactate release were significantly elevated, suggesting a shift toward aerobic glycolysis. Furthermore, mRNA expression of the glucose transporter Glut1 and lactate dehydrogenase A was markedly increased following SASH1 depletion, implying that PKM2's nuclear translocation facilitates its role in transcriptional regulation. To further investigate this interaction, this study designed a peptide to block the SASH1-PKM2 interaction and applied it in a mouse TBI model. Disrupting the SASH1-PKM2 interaction significantly reduced astrocytic activation and enhanced wound healing. In conclusion, our findings suggest that SASH1 sequesters PKM2 in astrocytes, and the blocking peptide releases PKM2, thereby promoting aerobic glycolysis and facilitating tissue repair after TBI. This study offers novel insights into the role of SASH1 in TBI.