Fig. 3: Schematic summary of HMGB1 signalling in the myocardium.
From: Scoping review of preclinical and clinical studies on the role of HMGB1 in heart disease
HMGB1 is a non-histone chromatin-binding protein in the nucleus. Under stress conditions or following injury, HMGB1 can be passively released into the extracellular space or transported to the cytoplasm and then actively secreted into the extracellular space by packing into intracellular vesicles (lysosomes or autophagosomes) and fusing with the cytoplasmic membrane12. HMGB1 can undergo post-translational modifications (PTM) affecting nuclear localisation signals (NLS) and nuclear export signal (NES) to facilitate translocation of nuclear HMGB1 to the cytoplasm11,12. These PTMs include acetylation, phosphorylation, methylation, N-glycosylation, and oxidation. The redox state of HMGB1 modulates function both intra- and extracellularly25,118,119. Conformational changes as a result of the disulfide bridge between C23 and C45 alter the affinity of HMGB1 for intracellular shuttling proteins and extracellular receptors. Intracellularly, upregulation of nuclear HMBG1 has been shown to be beneficial. The function of cytoplasmic HMGB1 depends on post-translational modifications and is not fully understood. Extracellular HMGB1 acts as an alarmin. frHMGB1 forms a heterocomplex with CXCL12 and signals via CXCR4 to promote chemotaxis and tissue repair. dsHMGB1 signals via TLR-2, TLR-4, and RAGE to promote the release of pro-inflammatory cytokines. The dsHMGB1–RAGE axis also activates platelets. Various strategies have been explored to inhibit HMGB1, including Box A, glycyrrhizin, anti-HMGB1 antibodies, or small interfering RNA. Box A acts as a competitive inhibitor of HMGB1, whereas glycyrrhizin or neutralising antibodies bind to the HMGB1. However, none of these approaches can target a specific redox form of HMGB1. Created in BioRender. Mao, S-H. (2026) https://BioRender.com/scr20ip frHMGB1 fully reduced HMGB1, dsHMGB1disulfide HMGB1.
