4-Methylumbelliferone, an Inhibitor of Hyaluronan Synthase, Prevents the Development of Oncological, Inflammatory, Degenerative, and Autoimmune Diseases

Abstract: Hyaluronic acid (HA) is the main structure-forming polymer of the extracellular matrix. HA metabolism plays an important role in intercellular interaction in healthy organism and in various pathologies. HA is synthesized by hyaluronan synthase (HAS); mammals have three highly homologous isoforms of this enzyme: HAS1, HAS2, and HAS3. No highly specific competitive inhibitors of HASs have been described so far. 4-Methylumbelliferone (4-MU), a natural coumarin compound, is commonly used to inhibit HA synthesis in vivo and in cell cultures. The review is focused on the molecular mechanisms underlying the therapeutic effects of 4-MU and discusses results of 4-MU application in tissue cultures and animal disease models, as well as in first clinical trials of this compound. It was found that along with receptors and transcription factors, one of the pharmacological targets of 4-MU is HAS2, which is most common isoform of HAS. Moreover, it is inhibition of HA synthesis that underlies the pharmacological effects of 4-MU in oncological, autoimmune, degenerative, and hypercompensated regenerative processes (fibrosis, scar formation). New clinical drugs based on specific HAS2 inhibitors will be the first-in-class compounds to treat a wide range of diseases.