Targeting MD2 in diseases: from structure and function to inhibitor development

Myeloid differentiation protein 2 (MD2) is an indispensable co-receptor for Toll-like receptor 4 (TLR4) and also serves as a key recognition protein for lipopolysaccharide (LPS). Binding of LPS to TLR4-MD2 complex triggers downstream signaling cascades that regulate the production of pro-inflammatory cytokines, thereby contributing to the pathogenesis of inflammation-related diseases such as acute lung injury, sepsis, and cardiac fibrosis. Targeting MD2 has emerged as an important therapeutic strategy for human diseases. Currently, significant progress has been made in the development of MD2 inhibitors, among which ACT001, TAK-242, and eritoran have entered clinical studies for the treatment of diffuse midline glioma, alcoholic hepatitis and septic shock, etc. In this review, we provide a systematic summary of reported MD2 inhibitors, focusing on their structural characteristics, biological functions, binding modes with MD2, and the role of MD2 in related diseases, with the goal of providing reference for the development of novel anti-inflammatory drugs.