Endothelial ferroptosis in blood–brain barrier dysfunction and neuroinflammation: mechanisms and immune–vascular crosstalk

Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation. In the central nervous system (CNS), most ferroptosis research has focused on neurons and glial cells, whereas the vulnerability of brain microvascular endothelial cells (BMECs) and its consequences for blood–brain barrier (BBB) integrity remain less clearly defined.

Because BMECs form the vascular interface between the circulation and the brain parenchyma, ferroptotic injury in this cell population may represent an immunovascular mechanism through which endothelial redox stress is translated into barrier dysfunction and neuroinflammatory amplification. In this review, we summarize molecular pathways that may promote or restrain BMEC ferroptosis, including iron handling, antioxidant defense mediated by the solute carrier family 7 member 11 (SLC7A11)–glutathione peroxidase 4 (GPX4) axis and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, lipid peroxidation, and junctional remodeling.

We then discuss how ferroptosis-associated endothelial injury may contribute to BBB leakage, damage-associated molecular pattern release, innate immune sensing, leukocyte recruitment, glial activation, and self-amplifying inflammatory feedback at the neurovascular interface.