Androgen receptor promotes arachidonic acid metabolism and angiogenic microenvironment in AFP-negative hepatocellular carcinoma

Zhilong Lin, Xiaofei Liu, Houwei Wang, Shumin Li, Ziqiang Miao, Jing Yang, Yuting Zhang, Kai Lei, Yifan Wu, Youmei Kang, Ruoyin Zheng, Zonglin Xie, Yixi Wen, Xiaoxue Ren, Chunxiao Liu, Alfred Sze-Lok Cheng, Yubin Xie, Shuling Chen, Ming Kuang, Sui Peng (), Zhenwei Peng () and Zihao Dai ()
Additional contact information
Zhilong Lin: The First Affiliated Hospital of Sun Yat-sen University
Xiaofei Liu: Sun Yat-sen University
Houwei Wang: The First Affiliated Hospital of Sun Yat-sen University
Shumin Li: Sun Yat-sen University
Ziqiang Miao: Sun Yat-sen University
Jing Yang: Sun Yat-sen University
Yuting Zhang: Sun Yat-sen University
Kai Lei: The First Affiliated Hospital of Sun Yat-sen University
Yifan Wu: Sun Yat-sen University
Youmei Kang: Sun Yat-sen University
Ruoyin Zheng: The First Affiliated Hospital of Sun Yat-sen University
Zonglin Xie: Sun Yat-sen University
Yixi Wen: Sun Yat-sen University
Xiaoxue Ren: Sun Yat-sen University
Chunxiao Liu: Sun Yat-sen University
Alfred Sze-Lok Cheng: The Chinese University of Hong Kong
Yubin Xie: Sun Yat-sen University
Shuling Chen: Sun Yat-sen University
Ming Kuang: The First Affiliated Hospital of Sun Yat-sen University
Sui Peng: Sun Yat-sen University
Zhenwei Peng: Sun Yat-sen University
Zihao Dai: The First Affiliated Hospital of Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Alpha-fetoprotein (AFP) is a classic biomarker for hepatocellular carcinoma (HCC). AFP-positive HCC (AFP+ HCC) has been intensively investigated; however, the genomic, transcriptomic and microenvironmental characteristics of AFP-negative HCC (AFP− HCC) remain to be deciphered. Here we show that tumors display mild differences in genetic alterations between AFP− HCC and AFP+ HCC patients, while AFP− HCC exhibits hyperactive arachidonic acid metabolism. Furthermore, the transcription activity of androgen receptor (AR) is significantly increased in AFP− HCC and plays a positive regulatory role in arachidonic acid metabolism and its metabolite 11,12-epoxyeicosatrienoic acid (11,12-EET). The tumor-derived 11,12-EET exhibits high affinity for EGFR that promotes the migration and tube formation of endothelial cells in vitro. Combination of lenvatinib and bicalutamide (an AR antagonist) enhances the therapeutic efficacy for AFP− HCC. Overall, we uncover the AR-mediated hyperactive arachidonic acid metabolism in AFP− HCC, and reveal AR-11,12-EET-EGFR axis-induced angiogenesis, providing a promising strategy of combined AR antagonist with lenvatinib for AFP− HCC treatment.

Date: 2025
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DOI: 10.1038/s41467-025-61448-z

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