4-Methylumbelliferone (4-MU)

4-Methylumbelliferone is a known synthetic inhibitor of hyaluronic acid (HA) ^{[1, 2]}. IC₅₀ values are in the proliferation assay were 0.65±0.04mM^[3].

4-Methylumbelliferone can inhibit the proliferation of Hepatocellular Carcinoma (HCC) cell lines (0.5mM , 48h) , induce apoptosis (5mM , 48h) , and inhibit the production of HA (Hyaluronan) ^[4]. Public database analysis predict that 4-Methylumbelliferone stimulated the activity of enzymes , which modulate protein processing (enzymes and transcription factors , including 13 members of the nuclear receptor superfamily regulating lipid and carbohydrate metabolism) , cell motility , membrane glycolipid composition and glycogen breakdown^[5].

4-Methylumbelliferone (6.5mg/g/day , 6 months , systemic oral administration) reduced perineuronal nets (PNNs) formation around neurons and enhanced memory retention in mice^[6]. 4-Methylumbelliferone (25mg/kg for 24 hours dissolved in DMSO/0.9% NaCl (1 : 4) by intraperitoneal injection) had a potential ability to attenuate the cardiac injury by reducing oxidative stress and inflammation in a TLR4/NF-κB/NLRP3-dependent mechanism^[7] .

4-Methylumbelliferone deregulates the tumor microenvironment by inhibiting HA synthesis^[2].

References:

[1]    LUO Y, YANG Z, YU Y, et al. HIF1alpha lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer [J]. Int J Biol Macromol, 2022, 222(Pt B): 2225-43.

[2]    VITALE D L, ICARDI A, ROSALES P, et al. Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy [J]. Front Oncol, 2021, 11(710061.

[3]    GARCIA-VILAS J A, QUESADA A R, MEDINA M A. 4-methylumbelliferone inhibits angiogenesis in vitro and in vivo [J]. J Agric Food Chem, 2013, 61(17): 4063-71.

[4]    PICCIONI F, MALVICINI M, GARCIA M G, et al. Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice [J]. Glycobiology, 2012, 22(3): 400-10.

[5]    TSITRINA A A, HALIMANI N, ANDREICHENKO I N, et al. 4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing [J]. International Journal of Molecular Sciences, 2023, 24(3):

[6]    JANA DUBISOVA  J S B, LUCIE SVOBODOVA , PAVOL MAKOVICKY , NOELIA MARTINEZ-VAREA , ANDA CIMPEAN , JAMES W FAWCETT , JESSICA C F KWOK , SARKA KUBINOVA. Oral treatment of 4-methylumbelliferone reduced perineuronal nets and improved recognition memory in mice [J]. 2022,

[7]    BISTOLETTI M, BOSI A, CAON I, et al. Involvement of hyaluronan in the adaptive changes of the rat small intestine neuromuscular function after ischemia/reperfusion injury [J]. Sci Rep, 2020, 10(1): 11521.

4-Methylumbelliferone是一种已知的合成透明质酸（HA）抑制剂^[1,2]。增殖试验的IC₅₀值为0.65±0.04mM^[3]。

4-Methylumbelliferone可抑制肝细胞癌（HCC）细胞系细胞增殖（0.5mM，48小时），诱导细胞凋亡（5mM，48小时），抑制透明质酸的产生^[4]。公共数据库分析预测，4-Methylumbelliferone能够刺激那些调节蛋白质加工（酶和转录因子，包括13个核受体超家族成员调节脂质和碳水化合物代谢）、细胞迁移、膜糖脂构成以及糖原分解的酶的活性^[5]。

4-Methylumbelliferone（6.5 mg/g/天，6个月，口服）减少了小鼠神经元周围神经网络（PNNs）的形成，增强了记忆保留^[6]。4-Methylumbelliferone（25mg/kg，溶解于DMSO/0.9%NaCl（1:4）中，腹腔注射24小时）通过TLR4/NF-κB/ nlrp53的依赖机制减轻氧化应激和炎症反应，具有减轻心脏损伤的潜在能力^[7]。

4- Methylumbelliferone通过抑制透明质酸（HA）的合成来扰乱肿瘤微环境^[2]。