Nuclear protein 1 protects against neonatal hypoxic-ischemic encephalopathy by inhibiting neuronal ferroptosis by improving iron storage.

Abstract

Recent studies have highlighted the role of ferroptosis in neuronal damage during neonatal hypoxic-ischemic encephalopathy (HIE). Nuclear protein 1 (NUPR1), a newly identified crucial modulator of ferroptosis, remains unexplored in the context of HIE. This study aimed to investigate whether NUPR1 modulates ferroptosis and influences hypoxic-ischemic brain injury through specific molecular mechanisms. NUPR1-knockdown neurons presented increased sensitivity to Erastin-induced neuronal ferroptosis, whereas NUPR1 overexpression conferred resistance. Notably, silencing NUPR1 exacerbated OGD/R-induced neuronal damage and ferroptosis, as evidenced by increased lipid peroxidation, malondialdehyde (MDA) levels, and iron concentrations, as well as decreased glutathione (GSH) levels and altered expression of ferroptosis-related proteins (elevated PTGS2 and reduced GPX4). Conversely, NUPR1 overexpression alleviated OGD/R-induced neuronal damage and ferroptosis. HIE animal model experiments demonstrated that NUPR1 overexpression mitigated brain damage, reduced infarct size, and decreased brain edema, which were correlated with diminished ferroptosis markers. Furthermore, NUPR1 knockdown reduced ferritin heavy chain 1 (FTH1) expression, whereas NUPR1 overexpression increased FTH1 levels, indicating a regulatory role in iron metabolism. Silencing FTH1 reversed the inhibitory effect of NUPR1 on neuronal ferroptosis. Collectively, our findings indicate that NUPR1 protects against ferroptosis in HIE, making it a potential therapeutic target for reducing neuronal injury associated with this condition. NUPR1 suppresses neuronal ferroptosis by increasing FTH1 expression and improving iron storage, enhancing our understanding of the mechanisms involved in ferroptosis in neonatal HIE.