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UGT2B15 Acts as a Critical Detoxification Barrier Against Chemi-Cal-Induced Hepatotoxicity and Carcinogenesis via the

Yiru Zhao1,2,3, Yin Wang1,2,3, Yu Li1,2,3

  • 1Guangdong Provincial Key Laboratory of Translational Chinese Medicine, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.

Cells
|May 13, 2026
PubMed

Insights

Mutations in detoxification enzymes (UGTs) are common in liver cancer (HCC). The androgen receptor (AR) regulates UGT2B15, a key enzyme protecting against liver injury and chemical carcinogenesis.

Area of Science:

  • Hepatology
  • Cancer Biology
  • Pharmacogenomics

Background:

  • Uridine diphosphate glucuronosyltransferases (UGTs) are crucial phase II detoxification enzymes.
  • Their role in hepatocellular carcinoma (HCC) and chemical carcinogenesis is not well understood.

Purpose of the Study:

  • Investigate the mutational landscape of liver-enriched UGT genes in HCC.
  • Determine the functional and clinical significance of UGT alterations in HCC development and progression.
  • Elucidate the regulatory mechanisms and protective roles of UGTs against chemical-induced liver injury.

Main Methods:

  • Targeted sequencing of ten liver-enriched UGT genes in a Chinese HCC cohort.
  • Quantitative mRNA and protein expression analysis.
  • Correlation analysis with patient survival data (TCGA cohorts).
  • Androgen receptor (AR) manipulation and reporter assays.
  • UGT2B15 knockdown in HCC cells followed by transcriptomic profiling.
  • In vitro and in vivo hepatotoxicity studies using carbon tetrachloride (CCl4) and ethanol.

Main Results:

  • High mutation frequencies observed in UGT2B15 (44.74%), UGT2B10 (36.84%), and UGT2B17 (26.32%) in HCC tumors.
  • Significant downregulation of UGT2B15 mRNA and protein levels in tumors.
  • Higher UGT2B15 expression correlated with improved overall survival in TCGA HCC cohorts.
  • AR identified as a direct transcriptional regulator of UGT2B15 and UGT2B17, induced by dihydrotestosterone (DHT).
  • UGT2B15 deficiency exacerbated CCl4- and ethanol-induced hepatotoxicity.

Conclusions:

  • Profound impairment of UGT-mediated detoxification in HCC.
  • The AR-UGT2B15 axis is a critical defense against chemical-induced liver injury.
  • UGT2B15 represents a potential chemopreventive target for carcinogen-exposed populations.
Keywords:
UGTscarcinogenhepatocellular carcinomaliver injurytargeted sequencing

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