Phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3] is a phosphorylated derivative of phosphatidylinositol 4 - phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which recruit and activate AKT in the plasma membrane (PM) to promote cellular survival. ORP5 anchors at the endoplasmic reticulum (ER) -PM contact sites and acts as a PI(4)P and PI(4,5)P2/phosphatidylserine (PS) exchanger. Here, a lipidomics analysis of the sensorimotor cortex revealed that transient middle cerebral artery occlusion (tMCAO) disturbs the homeostasis of phosphatidylinositols (PIs) and PS between the PM and ER. Conditional knockout mice showed that ORP5 contributes to this abnormal distribution. Abolishing the ORP5 gene signi ficantly inhibited apoptosis and autophagy. RNA sequencing and RNA pull down analyses con firmed a competing endogenous RNA pathway in which circ_0001449 sponges miR-124-3p and miR-32-5p to promote Osbpl5 translation. Our data showed that circRNA_0001449 regulates membrane homeostasis via ORP5 and is involved in the AKT survival pathway.