HMGB1 is a key therapeutic target for sterile inflammation and infection. It is a nuclear protein that is actively released by the innate immune system in response to pathogens or injury, and passively released during cell damage. HMGB1 activates innate immune responses through TLR4, leading to cytokine release and tissue damage. Targeting HMGB1 with neutralizing antibodies or inhibitors can reverse and prevent innate immune activation, reducing damage in various models of sterile and infectious inflammation. HMGB1 is involved in the pathogenesis of both sterile and infectious inflammation, acting as a signaling molecule that informs the body of damage or invasion. It mediates inflammatory responses such as fever, anorexia, and vascular leakage, and its activity is modulated by cytokines and pathogen-derived molecules. HMGB1 also interacts with receptors like RAGE and TLR4, which are crucial for its signaling and inflammatory effects. Studies show that HMGB1 is released during cell death, particularly apoptosis, and its release is regulated by redox-sensitive cysteine residues. HMGB1 plays a central role in the inflammatory response to sterile and infectious threats, and its inhibition can significantly reduce tissue damage and improve survival in conditions such as sepsis, pancreatitis, and arthritis. Therapeutic strategies targeting HMGB1 include neutralizing antibodies, antagonists, and inhibitors that block its release or activity. These approaches have shown promise in reducing inflammation and damage in various diseases, highlighting HMGB1's importance in immune regulation and its potential as a therapeutic target.HMGB1 is a key therapeutic target for sterile inflammation and infection. It is a nuclear protein that is actively released by the innate immune system in response to pathogens or injury, and passively released during cell damage. HMGB1 activates innate immune responses through TLR4, leading to cytokine release and tissue damage. Targeting HMGB1 with neutralizing antibodies or inhibitors can reverse and prevent innate immune activation, reducing damage in various models of sterile and infectious inflammation. HMGB1 is involved in the pathogenesis of both sterile and infectious inflammation, acting as a signaling molecule that informs the body of damage or invasion. It mediates inflammatory responses such as fever, anorexia, and vascular leakage, and its activity is modulated by cytokines and pathogen-derived molecules. HMGB1 also interacts with receptors like RAGE and TLR4, which are crucial for its signaling and inflammatory effects. Studies show that HMGB1 is released during cell death, particularly apoptosis, and its release is regulated by redox-sensitive cysteine residues. HMGB1 plays a central role in the inflammatory response to sterile and infectious threats, and its inhibition can significantly reduce tissue damage and improve survival in conditions such as sepsis, pancreatitis, and arthritis. Therapeutic strategies targeting HMGB1 include neutralizing antibodies, antagonists, and inhibitors that block its release or activity. These approaches have shown promise in reducing inflammation and damage in various diseases, highlighting HMGB1's importance in immune regulation and its potential as a therapeutic target.