Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide (Maas et al., 2017) and often results in long-lasting cognitive, behavioral, and emotional deficits, including depression and anxiety (Hiott and Labbate, 2002; Jorge et al., 2004). Increasing evidence suggests that the cognitive and behavioral deficits following TBI are associated with white matter injury (Filley and Kelly, 2018). However, the underlying mechanisms of white matter injury after TBI remain poorly understood.

Several studies have shown that ferroptosis following TBI can lead to cognitive and motor impairment (Kenny et al., 2019; Rui et al., 2021; Xie et al., 2019). Intracellular iron homeostasis is typically regulated by multiple molecular mechanisms, including iron uptake, export, and release (Bao et al., 2021). As the primary iron-chelating and storage protein in cells, ferritin plays a crucial role in iron metabolism by reducing the concentration of free iron. Nuclear receptor coactivator 4 (NCOA4) has been identified as a selective cargo receptor for ferritinophagy (Mancias et al., 2014), which facilitates the transport of ferritin for lysosomal degradation. Excessive ferritinophagy increases intracellular free iron levels, which could lead to ferroptosis. However, it is unclear whether ferritinophagy-induced ferroptosis is involved in white matter injury after TBI.

Integrated stress response inhibitor (ISRIB) is a small molecule that can reverse the effects of eIF2 phosphorylation in stressed cells, resulting in improved memory and spatial learning abilities in mice (Krukowski et al., 2020; Sharma et al., 2020; Sidrauski et al., 2013). However, ISRIB does not impact translation or mRNA synthesis in non-stressed cells (Sidrauski et al., 2015). Previous studies have demonstrated that ISRIB can improve long-term depression in Alzheimer’s disease (Hu et al., 2022; Zhang et al., 2022) and severe depression (Liu et al., 2020), as well as promote motor function recovery after spinal cord injury (Chang et al., 2022). Furthermore, ISRIB could reverse chronic cognitive deficits following TBI (Chou et al., 2017). These findings suggested that ISRIB was a potential therapeutic agent for neural injuries. However, whether a relationship between ISRIB and ferritinophagy was rarely mentioned and whether it has a repairing effect on white matter injury after TBI is unclear. In this study, we aimed to investigate the potential role of ferritinophagy in white matter injury following TBI and explore the effectiveness of ISRIB in mitigating this condition.