Targeting HMGB1 and Its Interaction with Receptors: Challenges and Future Directions.

High mobility group box 1 (HMGB1) is a nonhistone chromatin protein predominantly located in the nucleus. However, under pathological conditions, HMGB1 can translocate from the nucleus to the cytoplasm and subsequently be released into the extracellular space through both active secretion and passive release mechanisms. The distinct cellular locations of HMGB1 facilitate its interaction with various endogenous and exogenous factors, allowing it to perform diverse functions across a range of diseases. This Perspective provides a comprehensive overview of the structure, release mechanisms, and multifaceted roles of HMGB1 in disease contexts. Furthermore, it introduces the development of both small molecule and macromolecule inhibitors targeting HMGB1 and its interaction with receptors. A detailed analysis of the predicted pockets is also presented, aiming to establish a foundation for the future design and development of HMGB1 inhibitors.