Abstract:AIM: To investigate whether excessive glucocorticoid (GC) exposure disrupts retinal pigment epithelial (RPE) homeostasis through glucocorticoid receptor (GR)-dependent autophagy hyperactivation. METHODS: Human retinal pigment epithelial cell line (ARPE-19 cells) were exposed to GC (0–100 μmol/L, 48h). RESULTS: GC induced GR upregulation and mitochondrial translocation in a dose- and time-dependent manner, correlating with pathological autophagy activation. Key findings included: 1) tight junction disruption, evidenced by ZO-1 fragmentation, 2) reduction in phagocytic uptake efficiency, 3) mitochondrial shrinkage and autolysosome accumulation (TEM), 4) altered AMPK/mTOR signaling (p-AMPK up, p-mTOR down) associated with autophagosome formation, 5) elevated LC3-II levels confirming excessive autophagic flux. Critically, all GC-induced effects, including GR upregulation, signaling changes, and increased autophagy, were abolished by GR antagonism with RU486. CONCLUSION: This study shows that GR-dependent GC exposure induces autophagic flux with ultrastructural evidence suggestive of mitochondria-targeted autophagy and alters AMPK/mTOR signaling, correlating with RPE barrier collapse and phagocytic failure, a possible link to steroid-associated central serous chorioretinopathy (CSC).
