The potential of 4-Methylumbelliferone to be repurposed for treating liver fibrosis

Authors: CHEN, XI - Children'S Nutrition Research Center (CNRC); LI, HUIQIAO - Children'S Nutrition Research Center (CNRC); DENG, YANRU - Children'S Nutrition Research Center (CNRC); MENG, JIEYI - Children'S Nutrition Research Center (CNRC); ZHAO, SHANGANG - University Of Texas Health Science Center; WOOTON-KEE, CLAVIA RUTH - Children'S Nutrition Research Center (CNRC); GAO, XIA - Children'S Nutrition Research Center (CNRC); DONG, BINGNING - Baylor College Of Medicine; GUAN, DONGYIN - Baylor College Of Medicine; WU, CHAODONG - Texas A&M University; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center; ZHU, YI - Children'S Nutrition Research Center (CNRC)

Submitted to: Biomedicine and Pharmacotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/31/2025
Publication Date: 8/6/2025
Citation: Chen, X., Li, H., Deng, Y., Meng, J., Zhao, S., Wooton-Kee, C., Gao, X., Dong, B., Guan, D., Wu, C., Scherer, P.E., Zhu, Y. 2025. The potential of 4-Methylumbelliferone to be repurposed for treating liver fibrosis. Biomedicine and Pharmacotherapy. https://doi.org/10.1016/j.biopha.2025.118427.
DOI: https://doi.org/10.1016/j.biopha.2025.118427

Interpretive Summary: High doses of 4-methylumbelliferone (4-MU) reduced liver scarring in mice. However, this effect probably happened through several different mechanisms, not just by lowering hyaluronan. For example, 4-MU may also affect the gut microbiome. Because the treatment required very high doses and its exact mechanism is still unclear, 4-MU is unlikely to be a practical treatment for liver fibrosis in patients.

Technical Abstract: 4-Methylumbelliferone (4-MU) is the active component of hymecromone, a choleretic and antispasmodic drug with an excellent safety profile. In rodent studies, high doses of 4-MU are also used to inhibit the production of hyaluronan (HA), a biomarker of liver fibrosis. Further, 4-MU shows excellent efficacy in inhibiting liver fibrosis of different etiologies in animal studies, eliciting interest in its repurposing for this condition. However, 4-MU’s mechanism of action, and whether it inhibits liver fibrosis by impeding HA synthesis remains unclear. Using several transgenic mouse models with HA overproduction or degradation in different types of liver cells, we found that both directions of perturbation reduced liver fibrosis levels. In addition, degrading HA via hyal uronidase PH20 overexpression impaired liver function, manifested by increased serum aminotransferase (ALT) activity levels. These findings challenge both the role of HA modulation in 4-MU’s action and the strategy of targeting HA to treat liver fibrosis. Additional mouse models also excluded the possibility that 4-MU modulates intestinal farnesoid X receptor (FXR) to inhibit liver fibrosis. Ablation of gut microbiota partially abolishes 4- MU’s anti-liver fibrosis effect. However, the anti-liver fibrosis effect of 4-MU was lost in the lower-dose group. Based on these findings, we argue that the lack of efficacy of 4-MU at a translatable dose and the lack of a precise mechanism that allows improvement of 4-MU’s efficacy make 4-MU impractical for being repurposed as an anti- liver fibrosis treatment.