REVIEW article
Front. Neurol.
Sec. Neurotrauma
Phase-Targeted Erythropoietin Derivatives for Traumatic Brain Injury: Bridging Mechanisms to Precision Therapy
Provisionally accepted
- 1Yantaishan Hospital, yantai, China
- 2Yantai Hospital of Traditional Chinese Medicine, Yantai, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Traumatic brain injury (TBI) unfolds through a well-defined chronology—hyperacute excitotoxic and inflammasome bursts, acute apoptotic and blood–brain-barrier failure, and subacute neurovascular remodelling—that no single-pathway drug can adequately cover. Recombinant erythropoietin (EPO) limits secondary damage in animals, yet its erythropoietic drive and thrombotic liability have stalled clinical adoption. This review integrates structural biology, pharmacology and translational data on four engineered EPO derivatives—carbamylated EPO, asialo-EPO, darbepoetin alfa and the helix-B surface peptide (HBSP/cibinetide)—that decouple cytoprotection from red-cell stimulation. We first outline how specific modifications (carbamylation, desialylation, hyper-glycosylation or helix truncation) bias EPOR signalling toward PI3K–AKT and away from JAK2–STAT5. We then match each derivative to its optimal injury window. Meta-analyses of randomized trials suggest a possible trend toward lower short-term mortality without a consistent functional benefit or thrombotic signal. By integrating molecular mechanisms, experimental findings, and early clinical observations, this review outlines hypotheses and future trial frameworks for phase-targeted, erythropoietin-based neuroprotection. Further controlled studies are required to establish safety, efficacy, and optimal therapeutic timing before translation to routine clinical use.
Keywords: Traumatic Brain Injury, Erythropoietin derivatives, Neuroprotection, Protein Engineering, Secondary injury phases
Received: 14 Jul 2025; Accepted: 09 Dec 2025.
Copyright: © 2025 Sun, Song, Zhang, Zhang and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lu Zhou
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.