UGT2B15 Acts as a Critical Detoxification Barrier Against Chemi-Cal-Induced Hepatotoxicity and Carcinogenesis via the Androgen Receptor Axis - Research Paper Summary

Q: What mutation frequencies were observed for UGT genes in Chinese HCC tissues?

Targeted sequencing showed prominent mutation frequencies, especially UGT2B15 (44.74%), UGT2B10 (36.84%), and UGT2B17 (26.32%). Mutations mainly impaired enzymatic activity rather than protein stability.

Q: What happens to liver injury when UGT2B15 is lost?

UGT2B15 deficiency markedly exacerbated carbon tetrachloride (CCl4)- and ethanol-induced hepatotoxicity in vitro and in vivo by dysregulating carcinogen-metabolizing genes.

Sep 23, 2026

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Uridine diphosphate glucuronosyltransferases (UGTs) are key phase II detoxification enzymes, yet their mutation patterns and protective roles against chemical-driven carcinogenesis in hepatocellular carcinoma (HCC) were unclear. Targeted sequencing of ten liver-enriched UGT genes in 38 paired Chinese HCC tissues showed prominent mutations in UGT2B15 (44.74%) and major downregulation of UGT2B15 mRNA and protein in tumors. Higher UGT2B15 expression associated with improved survival in TCGA cohorts. Mechanistically, androgen receptor signaling directly regulated UGT2B15 and UGT2B17, while UGT2B15 loss worsened CCl4- and ethanol-induced hepatotoxicity. The study links an AR–UGT2B15 axis to impaired detoxification and identifies chemopreventive potential for carcinogen-exposed populations.

LanguageEnglish

CategoryHealthcare

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Pages18

Reading Time45 min

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What are the main findings?

What are the implications of the main findings?

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1. Introduction

Article UGT2B15 Acts as a Critical Detoxification Barrier Against Chemi-Cal-Induced Hepatotoxicity and Carcinogenesis via the Androgen Receptor Axis Yiru Zhao 1,2,3, Yin Wang 1,2,3, Yu Li 1,2,3, Shuqiang Liu 4, Zhen Jia 1,2,3, Ying Wang 1,2,3, Rong Zhang 1,2,3, Zhongqiu Liu 1,2,3,* and Linlin Lu 1,2,3, * Academic Editor: Mark A. Feitelson Received: 31 March 2026 Revised: 20 April 2026 Accepted: 29 April 2026 Published: 30 April 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Guangdong 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; [zhangrong@gzucm.edu.cn](zhangrong@gzucm.edu.cn) (R.Z.) 2 State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China 3 Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin 519000, China 4 School of Pharmaceutical Sciences, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan 250117, China * Correspondence: authors: [liuzq@gzucm.edu.cn](liuzq@gzucm.edu.cn) (Z.L.); [lllu@gzucm.edu.cn](lllu@gzucm.edu.cn) (L.L.) Highlights What are the main findings? • UGT2B15 is the most frequently mutated UGT gene (44.74%) in Chinese hepatocellular carcinoma patients, with mutations primarily impairing enzymatic activity rather than protein stability. • UGT2B15 expression is transcriptionally regulated by the androgen receptor (AR), establishing an AR–UGT2B15 detoxification axis in the liver. • UGT2B15 loss exacerbates CCl4-and ethanol-induced hepatotoxicity by dysregulating carcinogen-metabolizing genes including ADH1C, CYP1B1, MUC1, and PTGS2 . What are the implications of the main findings? • High UGT2B15 expression correlates with improved overall survival in HCC patients, suggesting its potential as a prognostic biomarker. • UGT2B15 acts as a critical chemopreventive barrier against chemical-induced liver injury, identifying it as a potential target for preventive interventions in carcinogenexposed populations. Abstract Uridine diphosphate glucuronosyltransferases (UGTs) are critical phase II detoxification enzymes; however, their mutational landscape and protective roles against chemical carcinogenesis in hepatocellular carcinoma (HCC) remain poorly defined. Here, targeted sequencing of ten liver-enriched UGT genes in 38 paired tissues from a Chinese HCC cohort revealed striking mutation frequencies in UGT2B15 (44.74%), UGT2B10 (36.84%), and UGT2B17 (26.32%) . This genomic instability was accompanied by a profound downregulation of UGT2B15 mRNA (9.02-fold decrease, p < 0.001) and protein levels (Z-score = 2.32, p = 0.0093) in tumors, with higher UGT2B15 expression correlating with improved overall survival in TCGA cohorts (HR = 1.724, p = 0.012) . Mechanistically, we identified the androgen receptor (AR) as a direct transcriptional regulator of UGT2B15 and UGT2B17, with dihydrotestosterone (DHT) inducing dose-dependent increases in their expression, thereby linking endocrine signaling to hepatic detoxification. Transcriptomic profiling following UGT2B15 knockdown in HCC cells revealed a significant enrichment in chemical carcinogenesis-related pathways. Crucially, UGT2B15 deficiency severely exacerbated carbon tetrachloride (CCl 4)-and ethanol-induced hepatotoxicity both in vitro and in vivo. Our study uncovers a profound impairment of UGT-mediated detoxification in HCC and establishes the AR–UGT2B15 axis as a critical barrier against chemical-induced liver injury, hig

FAQs

What mutation frequencies were observed for UGT genes in Chinese HCC tissues?

Targeted sequencing showed prominent mutation frequencies, especially UGT2B15 (44.74%), UGT2B10 (36.84%), and UGT2B17 (26.32%). Mutations mainly impaired enzymatic activity rather than protein stability.

How is UGT2B15 regulated and what detoxification axis is proposed?

UGT2B15 expression is transcriptionally regulated by the androgen receptor (AR). This establishes an AR–UGT2B15 detoxification axis in the liver, connecting endocrine signaling to hepatic detoxification.

What happens to liver injury when UGT2B15 is lost?

UGT2B15 deficiency markedly exacerbated carbon tetrachloride (CCl4)- and ethanol-induced hepatotoxicity in vitro and in vivo by dysregulating carcinogen-metabolizing genes.

Sep 23, 2026

Uploaded by Putri