Mechanism of HDAC2 regulating Nrf2 acetylation level in neuronal ferroptosis of neonatal rats with hypoxic-ischemic brain injury

Objective: We investigated the mechanism of histone deacetylase 2 (HDAC2) modulating nuclear factor erythroid 2-related factor 2 (Nrf2) acetylation level in neuronal Ferroptosis of hypoxic-ischemic brain injury (HIBI) neonatal rats.

Methods: The pathological damage and neuronal injury in the hippocampal CA1 region of HIBI neonatal rat models were assessed by HE and Nissl staining. Levels of neuron-specific Enolase (NSE), Glutathione Peroxidase 4 (GPX4), HDAC2, Nrf2, glutathione (GSH), Reactive Oxygen Species (ROS), malondialdehyde (MDA), active Fe²⁺, Nrf2 acetylation, and nuclear Nrf2 in hippocampal tissues were determined.

Results: HIBI induced upregulation of HDAC2 expression, causing hippocampal neuronal Ferroptosis in neonatal rats, as evidenced by dissolved hippocampal CA1 region, neuronatrophy, reduced number of neurons, abated NSE and GPX4 levels, decreased NeuN+/GPX4+ cells, diminished GSH level, and increased levels of ROS, MDA and active Fe²⁺. Inhibition of HDAC2 partially ameliorated neuronal Ferroptosis in HIBI neonatal rats. HDAC2 regulated Nrf2 expression and repressed Nrf2 nuclear translocation by mediating Nrf2 deacetylation. Inhibition of Nrf2 partially reversed the ameliorative effect of HDAC2 on neuronal Ferroptosis in HIBI neonatal rats.

Conclusion: HDAC2 modulated neuronal Ferroptosis in HIBI neonatal rats by mediating Nrf2 deacetylation.

Hypoxic-ischemic brain injury; deacetylation; ferroptosis; glutathione peroxidase 4; histone deacetylase 2; neonatal rats; nuclear factor erythroid 2-related factor 2.