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Engineered HMGB1 construct with tandem Box B domains promotes tissue regeneration without potential for inflammation

Lookup NU author(s): Professor Wyatt YueORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2026 The Authors. Fully reduced high-mobility group box 1 (HMGB1) binds CXCL12 and signals via CXCR4 when released into the extracellular space. It acts as a chemokine and transitions stem cells from quiescent G0 to a primed GAlert state. Cells in GAlert rapidly enter G1 in response to activating factors released by tissue injury to promote tissue repair. However, oxidative conversion of FR-HMGB1 into the disulfide form activates proinflammatory pathways via TLR-2, TLR-4 and RAGE. Peptide mapping and nuclear magnetic resonance (NMR) spectroscopy identified a conserved CXCL12-binding motif within each Box and adjacent flanking regions. We decoupled the regenerative and inflammatory functions using an engineered construct (dBB12L), comprising tandem Box B domains with a flexible linker. dBB12L exhibited CXCL12 binding and accelerated repair equivalent to FR-HMGB1. Importantly, dBB12L lacked detectable RAGE binding and did not signal via TLR-2 and TLR-4, establishing it as a potential therapeutic to promote tissue repair without deleterious inflammation.

Publication metadata

Author(s): Vinals Guitart A, Lee C, Espirito Santo AI, Ruan J-L, Mao S-H, William L, Redfield C, Fedorov O, Burgess-Brown NA, Yue WW, Nanchahal J

Publication type: Article

Publication status: Published

Journal: iScience

Year: 2026

Volume: 29

Issue: 8

Print publication date: 21/08/2026

Online publication date: 11/08/2026

Acceptance date: 24/07/2026

Date deposited: 18/08/2026

ISSN (electronic): 2589-0042

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.isci.2026.117140

DOI: 10.1016/j.isci.2026.117140

Data Access Statement: Requests for data reported in this paper should be directed to the corresponding author. This paper does not report original code. Any additional information required to re-analyze the data reported in this paper can be requested from the corresponding author.

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