The high mobility group (HMG)-box (HMGB) family belongs to the HMG protein superfamily that plays important roles in modulating chromatin structures. The HMGB family consists of four chromosomal proteins: HMGB1, HMGB2, HMGB3 and HMGB4. HMGB1 is ubiquitously expressed in high abundance (roughly 1 × 10 6 molecules per mammalian cell), whereas HMGB2, 3 and 4 are expressed at lower levels with restricted expression patterns. 1-3 Herein, we summarize the literature reports on the roles of HMGB1 in metabolic diseases and discuss the perspectives of targeting HMGB1 as a potential therapeutic approach.HMGB1 protein is both a nuclear factor and a secreted protein. 4 In the nucleus, HMGB1 serves as a transcriptional regulator that binds or bends DNAs or RNAs and promotes transcriptional complex assembly on specific gene targets. 5,6 For example, HMGB1 binds to the promoter region of TNF and promotes the assembly of the repressor NF-κB factor RelB, thus suppressing TNFα expression. 7 Upon infection or injury, HMGB1 has been shown to translocate from nucleus to the cytoplasm and could also be secreted by activated immune cells. 8 In addition, HMGB1 can be secreted by various cells, including hepatocytes, keratinocytes and granulocytes, under necrosis, DNA damage or oxidative stress. [9][10][11][12] Once secreted, HMGB1 functions as a ligand and binds to the receptor for advanced