Radiotherapy is a primary treatment for tumors in the head, neck, and intracranial regions(Wun Chin et al., 2024). However, it frequently results in complications, including radiation-induced brain injury (RIBI)(Yafeng et al., 2024). RIBI causes neuronal cell death, microvascular injury, and white matter demyelination(Zhuangzhuang et al., 2021). These effects contribute to cognitive decline, motor dysfunction, and psychological changes in affected patients(Chen et al., 2023).

Recent studies indicate that ferroptosis, a type of programmed cell death that relies on iron and lipid peroxidation, may be involved in the pathophysiology of RIBI(Xin et al., 2025). During radiotherapy, ionizing radiation generates a large quantity of reactive oxygen species (ROS). These ROS disrupt the intracellular antioxidant defense and lead to oxidative stress. This oxidative stress can trigger lipid peroxidation, which can result in the death of neuronal cells(Lifang et al., 2024). Research indicates that whole-brain irradiation (WBI) leads to mitochondrial changes and iron accumulation in neurons of the mouse hippocampus and cortex. These changes increase lipid peroxidation, which promotes an environment conducive to ferroptosis(Wenyu et al., 2024). Therefore, it is essential to better understand the mechanisms of radiation-induced brain injury (RIBI), particularly the role of ferroptosis, to develop effective prevention and treatment strategies for this significant complication in radiotherapy patients.

Maresin-1 (MaR1) is a natural lipid mediator with strong anti-inflammatory effects, making it potentially beneficial(Falsetta et al., 2023). Research has shown that MaR1 can reduce excessive reactive oxygen species and reduce lipid peroxidation during inflammation(Yongjing et al., 2024). Recent evidence indicates that MaR1 inhibits ferroptosis through the Nrf2/SLC7A11/GPX4 signaling pathway, thereby preventing acute liver injury caused by sepsis(Huiping et al., 2024; Pin et al., 2024). In the central nervous system, MaR1 reduces microglial activation and enhances learning and memory in models of sepsis-associated encephalopathy. This occurs via the regulation of ferroptosis through the SLC7A11/GPX4 pathway(Yongjing et al., 2024). However, the precise role of MaR1 in RIBI and its ability to reduce RIBI by targeting lipid peroxidation and ferroptosis remain unclear.

The retinoic acid receptor-related orphan receptor alpha (RORα), a receptor for MaR1, plays a crucial role in lipid metabolism as well as in neuronal differentiation, migration, and synaptic formation(Dong-Soon, 2020; Sarah et al., 2012). The NRF2 (nuclear factor erythroid 2-related factor 2) pathway is essential for regulating antioxidant responses, maintaining homeostasis, and mediating inflammation(Ching-Tung et al., 2025). NRF2 is an important transcription factor that activates antioxidant enzymes to combat oxidative stress(Ching-Tung et al., 2025). The interactions between RORα and NRF2, particularly in relation to lipid peroxidation-induced ferroptosis after RIBI and their connections with MaR1, require further investigation to clarify their roles in these pathophysiological processes.

This study aimed to determine whether MaR1 can inhibit ferroptosis caused by lipid peroxidation in radiation-induced brain injury (RIBI) through the RORα/NRF2 pathway, potentially improving prognosis. Understanding this mechanism will clarify the pathophysiology of radiation-induced brain injury and support the development of its prevention and treatment.