The article reviews the role of hyaluronan (HA) as an immune regulator in human diseases. HA, a major component of the extracellular matrix (ECM), plays a crucial role in tissue injury, repair, and inflammation. The accumulation and turnover of HA are hallmarks of tissue injury, and fragmented HA stimulates inflammatory gene expression in immune cells. HA binds to various cell surface proteins, including CD44, TLR2, and TLR4, to regulate inflammatory responses. HA also interacts with epithelial cells, providing protection against tissue damage. The review covers the biosynthesis, degradation, and signaling functions of HA, as well as the roles of HA-binding proteins such as CD44, RHAMM, TNFα-induced protein 6 (Tnfp6), brevican, neurocan, HABP1/C1QBP, and HARE. These proteins mediate HA's effects on inflammation, tissue injury, and repair. The article highlights the importance of HA in physiological and pathological conditions, emphasizing its potential as a therapeutic target in various diseases.The article reviews the role of hyaluronan (HA) as an immune regulator in human diseases. HA, a major component of the extracellular matrix (ECM), plays a crucial role in tissue injury, repair, and inflammation. The accumulation and turnover of HA are hallmarks of tissue injury, and fragmented HA stimulates inflammatory gene expression in immune cells. HA binds to various cell surface proteins, including CD44, TLR2, and TLR4, to regulate inflammatory responses. HA also interacts with epithelial cells, providing protection against tissue damage. The review covers the biosynthesis, degradation, and signaling functions of HA, as well as the roles of HA-binding proteins such as CD44, RHAMM, TNFα-induced protein 6 (Tnfp6), brevican, neurocan, HABP1/C1QBP, and HARE. These proteins mediate HA's effects on inflammation, tissue injury, and repair. The article highlights the importance of HA in physiological and pathological conditions, emphasizing its potential as a therapeutic target in various diseases.