摘要Although endogenous neural stem cells represent a promising target for noninvasive spinal cord injury repair,inflammatory lesion environments frequently trigger their death.Our prior work identified necroptosis as a key death pathway for endogenous neural stem cells migrating to spinal cord injury lesions.Rapamycin-insensitive companion of mTOR(Rictor;a core component of the mechanistic target of rapamycin complex 2[mTORC2]complex)regulates neural stem cell self-renewal and differentiation,and our preliminary data implicate it in spinal cord injury repair;however,its role in promoting endogenous neural stem cell survival post-spinal cord injury remains unclear.Here,we generated conditional endogenous neural stem cell-specific Rictor knockout mice using the Cre-loxP system.Although the endogenous neural stem cell-specific Rictor knockout mice displayed normal baseline spinal cord morphology and function,they exhibited impaired functional recovery after spinal cord injury compared with wild-type controls.This deficit correlated with elevated inflammatory responses and the increased susceptibility of endogenous neural stem cells to necroptosis.Mechanistically,lentiviral-mediated Rictor knockdown in neural stem cells in vitro impaired lysosomal function,leading to heightened sensitivity to tumor necrosis factor-alpha-and lipopolysaccharide-induced necroptosis.Collectively,these findings indicate that Rictor/mTORC2 signaling protects endogenous neural stem cells against receptor-interacting protein kinase 1-mediated necroptosis following spinal cord injury.Consequently,the modulation of intrinsic Rictor activity represents a potential therapeutic strategy to enhance endogenous neural stem cell survival and functional recovery post-spinal cord injury.