Spinal cord injury (SCI) is a common neurological disorder characterized by severe inflammation as well as eternal deficits in the nervous system. Primary injury induced by spinal cord trauma and secondary injury caused by a cascade of pathological events after primary injury remain two categories of SCI pathology. Of note, secondary injury is recognized as a pivotal event during SCI and a major therapeutic target of SCI (Hutson and Di Giovanni, 2019; Kjell and Olson, 2016; Quadri et al., 2020). Currently, the clinical therapeutic approaches towards SCI are limited to mainly deal with multiple complications, including severe inflammation in the nervous system and maladaptive plasticity after secondary injury, and offer supportive relief to patients with lifetime disability (Thuret et al., 2006; Khorasanizadeh et al., 2019). Hence, the better understanding of fundamental pathophysiology of SCI and the development of effective interventions are urgently required to improve clinical outcomes.

Endoplasmic reticulum (ER) stress is a crucial pathogenic event responsible for SCI-elicited cell death as well as neuronal dysfunction. Excessive ER stress can be observed around the injury area during secondary injury period of SCI (Cao and Kaufman, 2014; Bi et al., 2020). Under excessive ER stress state, pro-apoptotic markers such as C/EBP homologous protein (CHOP) are expressed in cells, thereby triggering cell apoptosis and aggravating SCI progression (Lee et al., 2014). Inhibition of ER stress has been established as a prospective approach to protect against SCI and accelerate function recovery following SCI (Huang et al., 2022; Wu et al., 2020; Liu et al., 2022). Protein kinase R (PKR) localized to the cytoplasm is one of the mediators of protein synthesis as well as an ER stress sensor. Currently, PKR inhibitors can suppress ER stress to attenuate pancreatic beta-cell insulin production (Yalcin et al., 2020), uncovering that PKR inhibitors can participate in and influence ER stress-related diseases, such as SCI. Existing evidence has shown that PKR is commonly presented in the spinal cord white and gray matter, and is predominantly expressed by microglia/macrophages (Li et al., 2015). Meanwhile, PKR is found to be well activated after SCI, demonstrating the involvement of PKR in SCI (Chang et al., 2022). However, the specific functions of PKR during SCI remain unclear.

Based on previous research above, we appraised the regulatory effects of PKR on SCI related to ER stress following the construction of in vivo models, and established the in vitro injury model in microglia to elucidate its potential mechanism of action. This study will provide theoretical support for developing alternative treatments of SCI.