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Yuanhuacine suppresses head and neck cancer growth by promoting ASCT2 degradation and inhibiting glutamine uptake

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Head and neck squamous cell carcinoma (HNSCC) cells exhibit a high dependency on glutamine metabolism, making it an attractive target. Despite the well-established link between glutamine reliance and tumor progression, the specific role of glutamine transporters in HNSCC remains poorly understood. The alanine-serine-cysteine transporter 2 (ASCT2), a key glutamine transporter, is overexpressed in HNSCC, and its silencing has been shown to reduce intracellular glutamine and glutathione levels, inhibiting tumor growth. These facts suggest that targeting ASCT2-mediated glutamine uptake could offer a promising therapeutic strategy for HNSCC. But no clinically approved drugs directly target ASCT2, and challenges such as the limited stability of antisense oligonucleotides persist. In this study we evaluated the correlation between ASCT2-mediate glutamine metabolism and its impact on HNSCC patients. We established a virtual screening method followed by cytotoxic assays to identify small molecules that specifically target ASCT2. Among the top 15 candidates, we identified yuanhuacine (YC) as the most potent antitumor compound with IC50 values of 1.43, 6.62, and 6.46 μM against HN6, CAL33, and SCC7 cells, respectively. We demonstrated that YC (0.3–5 μM) dose-dependently induced ASCT2 degradation by recruiting the E3 ubiquitin ligase RNF5, inhibiting glutamine uptake in HN6 cells. This disruption led to mitochondrial dysfunction and enhanced the therapeutic efficacy of YC. Our results highlight YC as a promising regulator of ASCT2-mediated glutamine metabolism in HNSCC.

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Fig. 1: ASCT2 overexpression was correlated with poor clinical outcomes in HNSCC patients.
Fig. 2: YC exerted anti-HNSCC effects by directly binding to ASCT2.
Fig. 3: YC promoted ASCT2 degradation.
Fig. 4: YC induced a glutamine metabolism crisis in HNSCC cells.
Fig. 5: YC induced mitochondrial damage and inhibited mitochondrial function.
Fig. 6: YC exhibited effective anti-tumor effects in vivo.
Fig. 7: Mechanism diagram.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No. 82322073, 82173846, 82304790, and 82430119), China Postdoctoral Innovative Talent Support Program (BX20220213), Shanghai Rising-Star Program (No.22QA1409100), Oriental Scholars of Shanghai (TP2022081), Jiangxi Province Thousand Talents Program (jxsq2023102168), Shanghai Shuguang Program (No. 24SG40), National Key R&D Program of China (Grant No. 2024YFC3506600), CAMS Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-3-009), Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (2060302), Shanghai Sailing Program (No. 22YF1445000, 23YF1442600), High-level Key Discipline of National Administration of Traditional Chinese Medicine (No. zyyzdxk-2023071), Innovation team of high-level local universities in Shanghai: Strategic Innovation Team of TCM Chemical Biology, Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine [No. 2023YZZ02], supported by the State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine. We thank the staff members of the Large-scale Protein Preparation System (https://cstr.cn/31129.02.NFPS.LSPS) at the National Facility for Protein Science in Shanghai (https://cstr.cn/31129.02.NFPS), for providing technical support and assistance in data collection and analysis. We acknowledge the online drawing software for figure creation (BioRender, https://biorender.com).

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  1. These authors contributed equally: Xin-yi Chen, Xin Chen, Xiao-hui Liang

Authors and Affiliations

  1. Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Xin-yi Chen, Xin Chen, Xiao-hui Liang, Dong Lu, Rong-rong Pan, Qing-yi Xiong, Xiao-xia Liu, Jia-yi Lin, Li-jun Zhang, Hong-zhuan Chen, Jin-mei Jin, Wei-dong Zhang & Xin Luan

  2. State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100700, China

    Wei-dong Zhang

  3. School of Pharmacy, Second Military Medical University, Shanghai, 200433, China

    Wei-dong Zhang

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Contributions

XYC, XC, and XHL: Writing—original draft. DL, QYX, XXL, and JYL: Methodology. RRP: Provision of compounds. LJZ and HZC: Investigation. JMJ, WDZ, and XL: Review & editing and conceptualization.

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Correspondence to Jin-mei Jin, Wei-dong Zhang or Xin Luan.

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Chen, Xy., Chen, X., Liang, Xh. et al. Yuanhuacine suppresses head and neck cancer growth by promoting ASCT2 degradation and inhibiting glutamine uptake. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01562-2

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