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(+)-JQ1 Upregulates SIRT3 to Suppress cGAS/STING Pathway-Mediated Neuronal Inflammation and Ferroptosis After
Qianqian Yu1,2, Jiahao Ou1,2, Yuqi Luo1,2
1Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Background:
Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurological disability and mortality in newborns, with limited therapeutic options beyond hypothermia. Bromodomain and extra-terminal domain (BET) proteins function as epigenetic readers that regulate gene expression by recognizing acetylated lysine residues on histones. Among BET inhibitors, (+)-JQ1 (JQ1) has recently garnered attention due to its potent anti-inflammatory and antioxidant properties. This study aims to investigate the neuroprotective effects of JQ1 and elucidate the underlying mechanisms in the context of HIE brain injury.
Methods:
We established an in vivo model via the modified Rice-Vannucci method, alongside an in vitro model using oxygen-glucose deprivation (OGD) in HT22 cells. Transcriptomic changes in cortical tissues during the acute phase after HIE were profiled through RNA sequencing. Western blot, immunofluorescence, immunohistochemistry, and transmission electron microscopy were employed to measure the levels of neuroinflammation and ferroptosis. Furthermore, SIRT3-knockdown HT22 cells under OGD conditions were used to validate the JQ1-mediated protective mechanisms.
Results:
JQ1 treatment significantly reduced cerebral infarction, edema, and neuronal loss, while improving emotional behavior and cognitive functions after HIE. It inhibited the cGAS-STING pathway, and alleviated ferroptosis by restoring GPX4 and system Xc⁻ activity while reducing iron overload. These effects were reversed by the SIRT3 inhibitor 3-TYP or SIRT3 siRNA.
Conclusion:
JQ1 exerts neuroprotective effects in neonatal hypoxic-ischemic encephalopathy by attenuating neuroinflammation and suppressing ferroptosis. We demonstrate that SIRT3 upregulation in the brain underlies the neuroprotective role of JQ1.
