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.