biostudies-literatureQiu ONational Natural Science Foundation of ChinaShanghai Association for Science and Technology109698https://www.ebi.ac.uk/biostudies/studies/S-EPMC11035374biostudies-literatureUnknown27(5)Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (<i>Lgmn</i>^+/+) mice following whole-brain irradiation. <i>Lgmn</i> knockout (<i>Lgmn</i>^-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuriScienceAsparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence.PMC11035374822727288177265420YF14262002014090024008227327882002630201409003000Xu LLi HZhou LQiu OLin YShi ZHuang RZhou ZZhang WYang XQiu YTang MLiao KWang SXie JHuang XMiao YZhao JfalseAsparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence.Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (<i>Lgmn</i>^+/+) mice following whole-brain irradiation. <i>Lgmn</i> knockout (<i>Lgmn</i>^-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neur2024-01-01T00:00:00Z2024 May2026-06-03T01:31:12.623Z2026-04-22T03:13:15.995ZS-EPMC110353743865519810.1016/j.isci.2024.109698