The ferroptosis-neuroinflammation feedback loop in traumatic brain injury: mechanisms and therapeutic implications.
TL;DR
A framework to comprehend the interplay between ferroptosis and inflammation is presented to guide the development of dual-targeted treatments in TBI and to guide the development of dual-targeted treatments in TBI.
Abstract
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, with secondary injury processes such as ferroptosis and neuroinflammation adding to its detrimental effects. Recent studies reveal a profound bidirectional interaction. On one hand, inflammation drives ferroptosis by disrupting iron homeostasis through the IL-6/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3)-hepcidin axis, impairing the system Xc-/glutathione (GSH)/GPX4 antioxidant system and promoting immune cell infiltration. Conversely, ferroptotic cells release damage-associated molecular patterns (DAMPs), including high-mobility group box 1 (HMGB1) and lipid peroxidation end-products like 4-hydroxynonenal (4-HNE), which activate toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling and fuel a neuroinflammatory vicious cycle. We further discuss emerging therapeutic approaches targeting this axis, including ferroptosis inhibitors (Fer-1, Lip-1), dual-regulatory agents (Annexin A5, melatonin, and H2S), and exosome-based delivery systems, while highlighting translational difficulties presented by the BBB and complex time windows. This review presents a framework to comprehend the interplay between ferroptosis and inflammation and to guide the development of dual-targeted treatments in TBI.