SETD1B promotes brain cell ferroptosis in ischemic stroke mice via increasing H3K4me3 enrichment on the Tfrc promoter.

AIMS

This study investigates the role of SET domain containing 1B (SETD1B), a histone lysine methyltransferase, in promoting ferroptosis induced by ischemic stroke through the upregulation of transferrin receptor 1 (TfR1).

MATERIALS AND METHODS

An ischemic stroke model was established in C57BL/6J mice by subjecting them to 1 h of ischemia followed by 24 h of reperfusion. Brain damage was assessed by neurological impairment and infarct volume. Levels of SETD1B, TfR1, total iron, Fe, lipid peroxidation (LPO), ferritin (FPN), and GPX4 were measured. In vitro, HT22 cells were subjected to 14 h of oxygen-glucose deprivation (OGD) followed by 24 h of reoxygenation. SETD1B knockdown was performed to assess its impact on ferroptosis.

KEY FINDINGS

In the ischemic stroke mice, SETD1B expression was elevated, accompanied by increased ferroptosis markers, including higher levels of TfR1, total iron, Fe, and LPO, as well as reduced levels of FPN and GPX4. These phenomena were observed in cultured HT22 cells under OGD/R conditions. SETD1B knockdown effectively reversed these effects, decreasing ferroptosis markers and reducing Tfrc expression via preventing H3K4me3 enrichment at the Tfrc promoter.

SIGNIFICANCE

These findings suggest that SETD1B enhances ferroptosis in stroke brain cells by a mechanism involving boosting H3K4me3 enrichment at the Tfrc promoter and subsequent upregulation of the expression of Tfrc. Targeting SETD1B may provide a therapeutic strategy for mitigating ferroptosis in stroke.