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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 &lt; 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 (CCl4)- 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\u2013UGT2B15 axis as a critical barrier against chemical-induced liver injury, highlighting its potential as a chemopreventive target in carcinogen-exposed populations.<\/jats:p>","DOI":"10.3390\/cells15090824","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:32:21Z","timestamp":1777555941000},"page":"824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["UGT2B15 Acts as a Critical Detoxification Barrier Against Chemi-Cal-Induced Hepatotoxicity and Carcinogenesis via the Androgen Receptor Axis"],"prefix":"10.3390","volume":"15","author":[{"given":"Yiru","family":"Zhao","sequence":"first","affiliation":[{"name":"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"},{"name":"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"},{"name":"Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Wang","sequence":"additional","affiliation":[{"name":"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"},{"name":"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"},{"name":"Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[{"name":"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"},{"name":"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"},{"name":"Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan 250117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Jia","sequence":"additional","affiliation":[{"name":"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"},{"name":"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"},{"name":"Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"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"},{"name":"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"},{"name":"Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhang","sequence":"additional","affiliation":[{"name":"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"},{"name":"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"},{"name":"Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Hengqin 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongqiu","family":"Liu","sequence":"additional","affiliation":[{"name":"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, 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