Naoqing formula alleviates acute ischaemic stroke-induced ferroptosis via activating /xCT/GPX4 pathway.

BACKGROUNDS

Ferroptosis is a form of regulated cell death. The accumulation of iron in the brain is linked to trigger ferroptosis after an ischaemic stroke (IS). Naoqing formula (NQ) is a traditional Chinese medicine metabolites with the clinical function of activating blood circulation, which is applied to treat IS clinically in China.

METHODS

Mice and SH-SY5Y cells were utilized to investigate the protective effects and the underlying mechanism of NQ against middle cerebral artery occlusion (MCAO) induced acute ischaemic stroke (AIS) and neuronal cellular ferroptosis caused by ferroptosis inducer Erastin and . Utilizing molecular biological techniques, transcriptomics, and proteomics analyses, the role of NQ in regulation and ferroptosis was evaluated through the pharmacologic inhibition of .

RESULTS

NQ attenuated AIS-induced neuronal damage and cerebral infarction by increasing cortical blood flow (CBF). Transcriptomics and proteomics analyses revealed that NQ might regulate lipid and iron metabolism through pathway. Additionally, NQ can protect AIS from ferroptosis by reducing oxidative stress and iron overload. Meanwhile, , solute carrier family 7 member 11 (SLC7A11; also known as xCT) and glutathione peroxidase 4 (GPX4) were upregulated in NQ-treated AIS mice. Consistent with the results , NQ led to ferroptosis resistance upon exposure to a ferroptosis-inducing compound through activation of /xCT/GPX4 pathway Notably, inhibition of expression by ML385 aggravated the ferroptotic events and weakened the neuroprotective effect of NQ as well as subsequently reduced the expression of xCT and GPX4.

CONCLUSION

This study demonstrated that NQ protected against AIS via suppression of ferroptosis and oxidative stress, which were largely dependent on the upregulation of pathway.