SP1 Aggravates Neonatal Hypoxic-Ischemic Brain Damage by Promoting Ferroptosis Through Transcriptional Upregulation of ACSL4
TL;DR
The SP1/ACSL4 axis critically aggravates neonatal hypoxic-ischaemic brain damage by promoting ferroptosis, representing a promising therapeutic target.
Abstract
Abstract Neonatal hypoxic-ischemic brain damage (HIBD) is a major cause of neurological disability. This study investigated the role of the transcription factor specificity protein 1 (SP1) and its target, Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), in regulating ferroptosis in neonatal HIBD. Using a neonatal mouse HIBD model and an in vitro neuronal oxygen-glucose deprivation/reperfusion (OGD/R) model, we applied gene knockdown/overexpression and pharmacological tools, analyzed via molecular and histological techniques. Ferroptosis was activated in HIBD. Hypoxic-ischaemic injury upregulated SP1, which transcriptionally activated ACSL4 by binding its promoter. SP1 knockdown attenuated neuronal and brain injury, reducing lipid peroxidation and iron accumulation while improving cell viability and cognitive function. These protections were abolished by ACSL4 overexpression or erastin co-treatment, and were associated with suppression of the ACSL4-dependent ferroptotic pathway. The SP1/ACSL4 axis critically aggravates neonatal hypoxic-ischaemic brain damage by promoting ferroptosis, representing a promising therapeutic target.