Lysine Demethylase 5B Alleviates Neuroinflammation in Ischemic Stroke by Repressing Steap4

Six-transmembrane epithelial antigen of prostate 4 (Steap4) has been suggested as a potential marker for reactive astrocytes. This investigation focuses on the role of Steap4 in ischemic stroke (IS) and its regulator in this context. A mouse model of IS was generated using middle cerebral artery occlusion (MCAO). Additionally, mouse astrocytes that underwent oxygen-glucose deprivation (OGD) were utilized for in vitro investigations. Steap4 was found to be upregulated in the brain of MCAO-challenged mice and OGD-challenged astrocytes. Steap4 silencing reduced infarct size and alleviated IS-associated pathological exacerbations in mice, as well as ameliorated A1 skewing of astrocytes and inflammatory cytokine secretion both in vivo and in vitro. Lysine demethylase 5B (Kdm5b), identified as an upstream regulator of Steap4, was poorly expressed in IS/OGD models. Kdm5b overexpression repressed Steap4 transcription by removing H3K4me3 modification, thus alleviating pro-inflammatory activation of astrocytes and neuroinflammation. However, Kdm5b's protective effects were diminished upon Steap4 restoration in mice or astrocytes. In conclusion, this study suggests that the loss of Kdm5b leads to aberrant upregulation of Steap4, contributing to pro-inflammatory activation of astrocytes and brain damage in IS.