ACCESSORY DNA REPAIR PROTEIN MRI SHAPES NEUROINFLAMMATORY RESPONSE IN HIE

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of infant mortality and lifelong neurological disability. Hypoxia-ischemia (HI) induces severe DNA damage, particularly double-strand breaks (DSBs), primarily repaired via the Non-Homologous End Joining (NHEJ) pathway. The accessory NHEJ protein Modulator of Retroviral Infections (MRI) has emerged as a potential therapeutic target, yet its role in neonatal brain injury remains unclear. Here, we investigated MRI-mediated mechanisms in neuroinflammation and neuroprotection using advanced mouse and human experimental stroke models. Neonatal MRI-knockout (MRI-KO) mice exhibited severe brain tissue loss following HI. Single-nucleus RNA sequencing (snRNA-seq) revealed enhanced gliovascular expansion, principal neuron loss, and dysregulation of inflammatory, extracellular matrix, synaptic, and repair pathways. High-resolution imaging confirms profound neuronal and glial alterations in MRI-deficient hippocampus. Additionally, we established a human brain organoid HI model and monitored dynamic cellular responses using live-cell imaging. Our findings identify MRI as a critical regulator of neuroinflammation and neuroprotection after HI, highlighting its potential as a therapeutic target for neonatal HIE.