Endoplasmic reticulum stress-mediated cell death in spinal cord injury: from molecular mechanisms to therapeutic applications

Spinal cord injury (SCI) is a disabling central nervous system injury that can lead to permanent loss of motor and sensory function below the level of injury. Currently, symptoms are primarily alleviated and endogenous repair mechanisms are enhanced through surgical decompression, spinal fixation, hyperbaric oxygen therapy, and drug therapy, but these methods do not directly promote nerve regeneration and functional recovery. The endoplasmic reticulum is an important organelle that plays a crucial role in maintaining cellular homeostasis. Cell death is a significant pathological event in SCI, which further worsens the microenvironment at the injury site, leading to neurological dysfunction and affecting the clinical outcomes of patients. Adverse external stimuli can induce endoplasmic reticulum stress (ERS) in the body. ERS affects cellular homeostasis and fate by activating the unfolded protein response (UPR) and mainly participates in the pathological process of SCI through regulating autophagy, apoptosis, ferroptosis, necroptosis, and other cell death programs. Current evidence suggests that cell death induced by ERS may be an important pathological mechanism determining the prognosis and outcome of SCI. This article systematically reviews the research progress on ERS and UPR in the regulation of cell death in SCI. We focus on integrating the evidence and possible mechanisms linking ERS with four typical modes of cell death. Furthermore, we summarize advances in understanding the involvement of ERS/UPR in processes including inflammation amplification, mitochondrial dysfunction, oxidative stress, and nerve repair in SCI. On this basis, this article summarizes potential intervention targets and therapeutic strategies, aiming to provide a clearer integrative framework for understanding the pathological mechanisms of SCI and to offer reference directions for subsequent basic research and clinical translational studies.