YLKTT, a potent biopeptide that ameliorates oxygen-glucose deprivation-induced neuronal cell ferroptosis by ACSL4/GPX4 and SLC7A11/GPX4 axis.

OBJECTIVES

Shuxuetong injection (SXT) treats cerebral ischemic injury by inhibiting apoptosis. However, the specific active ingredient responsible for this effect and its mechanism of action remain unclear.

METHODS

In previous research, we identified the small peptide YLKTT in SXT, which has shown protective effects on astrocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). In this study, we utilized transcriptomics technology to predict the specific target genes and pathways of YLKTT in the context of stroke treatment. We further validated these predictions through RT-PCR, lipid peroxidation assays, Western blotting, and other related methods.

KEY FINDINGS: The transcriptomics results indicated that YLKTT could further alleviate ischemia-reperfusion injury by inhibiting ferroptosis, with the specific pathway likely involving the regulation of glutathione peroxidase 4 (GPX4) by ACSL4 and SLC7A11. Experimental results demonstrated that YLKTT interfered with the SLC7A11/GPX4 and ACSL4/GPX4 pathways, thereby enhancing antioxidant capacity, inhibiting the accumulation of lipid peroxidation, and ultimately reversing OGD-induced ferroptosis. Additionally, erastin significantly reduced SLC7A11 mRNA and protein levels and decreased GPX4 levels, while YLKTT was able to reverse these changes.

CONCLUSIONS

YLKTT can exert anti-ferroptosis effects through the ACSL4/GPX4 and SLC7A11/GPX4 pathways, thereby improving the treatment of cerebral ischemic injury.