HMGB1 as biomarker and drug target

High Mobility Group Box 1 protein was discovered as a nuclear protein, but it has a “second life” outside
the cell where it acts as a damage-associated molecular pattern. HMGB1 is passively released or actively
secreted in a number of diseases, including trauma, chronic inflammatory disorders, autoimmune diseases
and cancer. Extracellular HMGB1 triggers and sustains the inflammatory response by inducing
cytokine release and by recruiting leucocytes. These characteristics make extracellular HMGB1 a key
molecular target in multiple diseases. A number of strategies have been used to prevent HMGB1 release
or to inhibit its activities. Current pharmacological strategies include antibodies, peptides, decoy receptors
and small molecules. Noteworthy, salicylic acid, a metabolite of aspirin, has been recently found
to inhibit HMGB1. HMGB1 undergoes extensive post-translational modifications, in particular acetylation
and oxidation, which modulate its functions. Notably, high levels of serum HMGB1, in particular
of the hyper-acetylated and disulfide isoforms, are sensitive disease biomarkers and are associated with
different disease stages. In the future, the development of isoform-specific HMGB1 inhibitors may potentiate
and fine-tune the pharmacological control of inflammation. We review here the current therapeutic
strategies targeting HMGB1, in particular the emerging and relatively unexplored small molecules-based
approach.