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Increasing evidence indicates that peroxisome proliferator-activated receptors (PPARs) play neuroprotective roles in various neurodegenerative disease models in vivo and in vitro. However, the underlying mechanisms remain unclear. Astrocyte proliferation is a key process in neural development and plays significant roles in the regeneration of neural tissue after a penetrating injury. Corticosterone can significantly reduce the expression of glial fibrillary acid protein (GFAP) in cultured rat hippocampal astrocytes in vitro, and induce astrocytic dysfunction. Our research found that corticosterone treatment resulted in astrocyte damage and reduced the expression of PPARβ/δ. GW0742, a selective and high-affinity PPARβ/δ agonist, attenuated the corticosterone-induced astrocyte damage, but also significantly reversed the increase in the expression of GRP78 and CHOP, the two predominant proteins in endoplasmic reticulum (ER) stress. Moreover, GW0742 decreased the levels of caspase-12 and cleaved caspase-3, thereby protecting astrocytes against corticosterone-induced astrocyte apoptosis. We then confirmed that GRP78 was a target gene of microRNA-181a and found that PPARβ/δ activation increased microRNA-181a levels. Finally, we demonstrated that PPARβ/δ activation by GW0742 noticeably inhibited the activities and expression of DNA methyltransferases, and reduced the corticosterone-induced CpG island hypermethylation of microRNA-181a1 in astrocytes. Therefore, the present study is the first to reveal that PPARβ/δ activation suppresses CpG island hypermethylation-associated silencing of microRNA-181a and thereby protects against ER stress-induced damage in astrocytes. Our findings suggest that PPARβ/δ activation in astrocytes might be a promising target for regulating ER stress-induced astrocytic injury.PPARβ/δ is the dominant subtype expressed in the primary cultured astrocytes.PPARβ/δ activation protects against corticosterone-induced astrocyte damage.PPARβ/δ activation protects against ER stress-induced apoptosis of astrocytes.PPARβ/δ activation up-regulates miR-181a levels in astrocytes.PPARβ/δ activation inhibits Dnmts and decreases CpG island methylation of MiR-181a1.