Chen Xi, Li Huiqiao, Deng Yanru, Meng Jieyi, Zhao Shangang, Wooton-Kee Clavia Ruth, Gao Xia, Dong Bingning, Guan Dongyin, Wu Chaodong, Scherer Philipp E, Zhu Yi
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
bioRxiv. 2025 May 23:2025.05.19.654778. doi: 10.1101/2025.05.19.654778.
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 hyaluronidase 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, and the high dose's effect in reducing ALT disappeared over time despite its liver fibrosis-reducing effect. Based on these findings, we argue that the lack of efficacy of 4-MU at a translatable dose and lack of a clear mechanism that allows further improvement of 4-MU's efficacy make 4-MU impractical for development as an anti-liver fibrosis treatment.
4-甲基伞形酮（4-MU）是利胆解痉药物羟甲香豆素的活性成分，具有出色的安全性。在啮齿动物研究中，高剂量的4-MU还用于抑制透明质酸（HA）的产生，HA是肝纤维化的生物标志物。此外，在动物研究中，4-MU在抑制不同病因引起的肝纤维化方面显示出优异的疗效，引发了将其重新用于治疗这种病症的兴趣。然而，4-MU的作用机制以及它是否通过阻碍HA合成来抑制肝纤维化仍不清楚。使用几种在不同类型肝细胞中HA产生过多或降解的转基因小鼠模型，我们发现这两种干扰方向均降低了肝纤维化水平。此外，通过透明质酸酶PH20过表达降解HA会损害肝功能，表现为血清转氨酶（ALT）活性水平升高。这些发现对HA调节在4-MU作用中的作用以及靶向HA治疗肝纤维化的策略都提出了挑战。其他小鼠模型也排除了4-MU通过调节肠道法尼醇X受体（FXR）来抑制肝纤维化的可能性。肠道微生物群的消融部分消除了4-MU的抗肝纤维化作用。然而，4-MU在低剂量组中失去了抗肝纤维化作用，高剂量在降低ALT方面的作用随着时间的推移消失了，尽管其仍有减轻肝纤维化的作用。基于这些发现，我们认为4-MU在可转化剂量下缺乏疗效，且缺乏能进一步提高其疗效的明确机制，这使得4-MU作为抗肝纤维化治疗药物进行开发不切实际。
