Molecular insights into the multifaceted functions and therapeutic targeting of high mobility group box 1 in metabolic diseases.

HMGB1 is a ubiquitously expressed protein localized in nucleus, cytoplasm, as well as secreted into extracellular space. Nuclear HMGB1 binds to DNAs and RNAs, regulating genomic stability and transcription. Cytoplasmic HMGB1 regulates autophagy through binding to core autophagy regulators. Secreted extracellular HMGB1 functions as a ligand to various receptors (RAGE and TLRs, etc.), regulating multiple signalling pathways, such as MAPK, PI3K and NF-κB signallings. Trafficking and localization of HMGB1 across cellular compartments could be regulated by its posttranslational modifications, which fine-tune its functions in metabolic diseases, inflammation and cancers. The current review examines the up-to-date findings pertaining to the biological functions of HMGB1, with focus on its posttranslational modifications and roles in downstream signalling pathways involved in metabolic diseases. This review also discusses the feasibility of targeting HMGB1 as a potential pharmacological intervention for metabolic diseases.