Ischemic stroke remains as a major cause for disability and death in the world. Long non-coding RNA (lncRNA) cardiac hypertrophy-related factor (CHRF) has been suggested as a crucial modulator in cardiac injury and various human cancers. Nevertheless, its effects and mechanism on ischemic stroke remains unclear. In this study, we found that CHRF was significantly correlated with miR-126, and miR-126 expression was decreased in the ischemic core following ischemia, while CHRF expression was increased according to the in vivo and in vitro experiments. Additionally, miR-126 significantly reduced oxygen-glucose deprivation and reoxygenation (OGD/R)-triggered apoptosis using TUNEL and flow cytometry analysis. Moreover, CHRF played as a competing endogenous RNA (ceRNA) and competed with Sex-determining region Y box 6 (SOX6) to direct binding with miR-126, subsequently regulating ischemic neuronal death. CHRF knockdown in vivo markedly prevented ischemic damage and alleviated neurological dysfunctions. Thereby, these results revealed a new molecular mechanism of lncRNA CHRF through targeting miR-126/SOX6 signaling to modulate ischemic neuronal injury, providing solid evidence to develop promising therapeutic strategies against cerebral ischemic stroke. (C) 2019 Published by Elsevier Inc.