ISRIB improves white matter injury following TBI by inhibiting NCOA4-mediated ferritinophagy

Abstract Traumatic brain injury (TBI) often results in persistent neurological dysfunction, which is closely associated with white matter injury. While the mechanisms underlying white matter injury after TBI remain unclear, recent research has implicated ferroptosis, a form of programmed cell death, in cognitive impairment after TBI. Ferritinophagy, a selective autophagic process that degrades ferritin and releases free iron. Here, we established a rat model of TBI and examined the expression of NCOA4, which mediates ferritin degradation through autophagy in lysosomes, to investigate whether ferritinophagy contributes to white matter injury after TBI. Our results showed that NCOA4 was overexpressed in the rat model of TBI, and knockdown of NCOA4 using shNCOA4 lentivirus infection inhibited ferroptosis induced by ferritinophagy. Furthermore, we found that treatment with ISRIB, a small molecule that selectively inhibits the integrated stress response, attenuated NCOA4-mediated ferritinophagy and improved white matter injury. These findings suggest that NCOA4-mediated ferritinophagy is a critical mechanism underlying white matter injury after TBI, and that ISRIB may hold promise as a therapeutic agent for treating this injury.