miR-7a-5p attenuates hypoxic-ischemic encephalopathy by suppressing PARP1-mediated parthanatos

Abstract

Hypoxic-ischemic encephalopathy (HIE) causes severe neonatal brain injury, with PARP1 hyperactivation implicated in neuronal death. Using a rat HIE model and glutamate-exposed HT22 neurons, we found that miR-7a-5p is significantly downregulated in both peripheral blood and the injured cortex of HIE rats. PARP1 hyperactivation triggered parthanatos, characterized by PAR polymer accumulation and apoptosis-inducing factor (AIF) nuclear translocation, without activating caspase-dependent apoptosis. Luciferase assays confirmed direct targeting of miR-7a-5p to the 3′ UTR of PARP1, suppressing its expression. Exogenous miR-7a-5p reduces infarction volume, improves neural morphology, and preserves neurological function recovery in HIE rats. In vitro , miR-7a-5p overexpression or pharmacological PARP1 inhibition attenuated glutamate-induced neuronal death, mitochondrial membrane potential (MMP) loss, ROS overproduction, and PAR/AIF dysregulation. Crucially, PARP1 agonist MNNG reversed miR-7a-5p-mediated neuroprotection, establishing the indispensability of the miR-7a-5p/PARP1 axis. miR-7a-5p is a key regulator of parthanatos, suppressing PARP1 hyperactivation, mitigating mitochondrial dysfunction, and offering a therapeutic target for HIE.