STC1 downregulation promotes ferroptosis in human brain microvascular endothelial cells: implications for moyamoya...

Moyamoya disease (MMD) is a rare progressive cerebrovascular disorder with incompletely understood pathological mechanisms. This study aimed to investigate the relationship between peripheral blood Stanniocalcin-1 (STC1) expression and MMD and to explore its potential molecular mechanisms. We performed RNA-sequencing on peripheral blood from MMD patients, cross-validated with GEO database datasets, and measured STC1 protein levels via ELISA in 30 MMD patients. To simulate the MMD microenvironment, we established a hypoxia model in human brain microvascular endothelial cells (hBMECs) and knocked down STC1 using AAV-mediated transfection. Key findings related to ferroptosis and oxidative stress were validated using qPCR, Western blot, and biochemical assays. Our analysis revealed significantly decreased STC1 expression in the peripheral blood of MMD patients, and ROC curve analysis identified STC1 as a potential biomarker. In our in vitro model, hypoxic conditions reduced STC1 expression in hBMECs. STC1 knockdown led to decreased cell viability, increased LDH release, and transcriptomic alterations enriched in the ferroptosis pathway. Specifically, STC1 knockdown resulted in the dysregulation of ferroptosis-related proteins, increased malondialdehyde (MDA) expression, and a decreased GSH/GSSG ratio. Crucially, these pro-ferroptotic effects, along with the loss of cell viability, were reversed by both STC1 re-expression and treatment with ferroptosis inhibitors. In conclusion, STC1 expression is downregulated in MMD patients, and its reduction may contribute to MMD pathogenesis by promoting ferroptosis in brain microvascular endothelial cells. STC1 may serve not only as a potential biomarker for MMD but also as a novel therapeutic target for this disease.