Traumatic brain injury (TBI) is an important cause of death and disability in young people worldwide without effective treatment. Ferroptosis was recently reported to be related to TBI and provided a potential target for developing new therapeutic strategies, but how it influenced TBI and the underlying mechanism were still unclear. Here, with multimodality of methods, ferroptosis was demonstrated to mainly occur in acute TBI. Further, we found that hyaluronic acid (HA), a natural extracellular matrix (ECM) material, could markedly and specifically inhibit ferroptosis in cells and TBI mice. Preblocking the HA-receptor interaction or CRISPR/Cas9-based gene deletion of HA putative receptors neurocan (NCN) and CD44 abolished the anti-ferroptosis effect of HA. Importantly, it was demonstrated that CD44 was significantly up regulated by tens of folds in the focus area of TBI. Through intravenous injection of Cy5-HA nanoconjugates, it was shown that HA could effectively bind to the TBI site like a targeting nanodrug and then, significantly reduced brain damage and behavioral defects. Collectively, we demonstrated HA as the natural anti-ferroptosis material which acted through receptor-mediated intrinsic signaling pathways, and developed a new therapeutic avenue for acute TBI treatment. Moreover, the new function of HA revealed in the study confirmed the existence of extracellular regulation of ferroptosis, and would largely promote the development of novel nanomaterials or nanodrugs for ferroptosis-related tissue injuries. (c) 2022 Elsevier Ltd. All rights reserved.