Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs <i>de novo</i> synthesis of glutathione

Fu'an Xie; Yujia Niu; Xiaobing Chen; Xu Kong; Guangting Yan; Aobo Zhuang; Xi Li; Lanlan Lian; Dongmei Qin; Quan Zhang; Ruyi Zhang; Kunrong Yang; Xiaogang Xia; Kun Chen; Mengmeng Xiao; Chunkang Yang; Ting Wu; Ye Shen; Chundong Yu; Chenghua Luo; Shu-Hai Lin; Wengang Li

doi:10.1016/j.jpha.2024.101068

Volume 15 Issue 1

Feb. 2025

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Fu'an Xie, Yujia Niu, Xiaobing Chen, Xu Kong, Guangting Yan, Aobo Zhuang, Xi Li, Lanlan Lian, Dongmei Qin, Quan Zhang, Ruyi Zhang, Kunrong Yang, Xiaogang Xia, Kun Chen, Mengmeng Xiao, Chunkang Yang, Ting Wu, Ye Shen, Chundong Yu, Chenghua Luo, Shu-Hai Lin, Wengang Li. Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione[J]. Journal of Pharmaceutical Analysis, 2025, 15(1): 101068. doi: 10.1016/j.jpha.2024.101068

Citation:

Fu'an Xie, Yujia Niu, Xiaobing Chen, Xu Kong, Guangting Yan, Aobo Zhuang, Xi Li, Lanlan Lian, Dongmei Qin, Quan Zhang, Ruyi Zhang, Kunrong Yang, Xiaogang Xia, Kun Chen, Mengmeng Xiao, Chunkang Yang, Ting Wu, Ye Shen, Chundong Yu, Chenghua Luo, Shu-Hai Lin, Wengang Li. Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione[J]. Journal of Pharmaceutical Analysis, 2025, 15(1): 101068. doi: 10.1016/j.jpha.2024.101068

Citation:

Fu'an Xie, Yujia Niu, Xiaobing Chen, Xu Kong, Guangting Yan, Aobo Zhuang, Xi Li, Lanlan Lian, Dongmei Qin, Quan Zhang, Ruyi Zhang, Kunrong Yang, Xiaogang Xia, Kun Chen, Mengmeng Xiao, Chunkang Yang, Ting Wu, Ye Shen, Chundong Yu, Chenghua Luo, Shu-Hai Lin, Wengang Li. Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione[J]. Journal of Pharmaceutical Analysis, 2025, 15(1): 101068. doi: 10.1016/j.jpha.2024.101068

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Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione

doi: 10.1016/j.jpha.2024.101068

a. Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China;
b. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China;
c. Department of Retroperitoneal Tumor Surgery, Peking University International Hospital, Beijing, 102206, China;
d. School of Public Health, Harvard University, Boston, MA, 02115, USA;
e. Department of Laboratory Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, China;
f. National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, 361102, China;
g. Laboratory of Biochemistry and Molecular Biology Research, Department of Clinical Laboratory, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, China;
h. Department of Hepatobiliary Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China;
i. Department of General Surgery, Peking University People's Hospital, Beijing, 100032, China;
j. Department of Gastrointestinal Surgical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, China;
k. Department of Management, Jiang Xia Blood Technology Co., Ltd., Shanghai, 200000, China

Funds:

We thank Haiping Zheng at the Central laboratory, School of Medicine, Xiamen University, China for providing scientific and technical support. This work was supported by grants from the National Natural Science Foundation of China (Grant NOs.: 82272935, 91957120 and 21974114), the Postdoctoral Fellowship Program of CPSF (Program No.: GZC20240901), the Xiamen Medical Industry Combined Guidance Project, China (Project No.: 3502Z20244ZD2022), the Scientific Research Foundation for Advanced Talents, Xiang'an Hospital of Xiamen University, China (Grant No.: PM20180917008), the Fundamental Research Funds for the Central Universities, China (Grant No.: 20720210001) and Major Science and Technology Special Project of Fujian Province, China (Project No.: 2022YZ036012), Joint Laboratory of School of Medicine, Xiamen University-Shanghai Jiangxia Blood Technology Co., Ltd., China (Grant No.: XDHT2020010C), and Joint Research Center of School of Medicine, Xiamen University-Jiangsu Charity Biotech Co., Ltd., China (Grant No.: 20233160C0002).

Received Date: Mar. 19, 2024
Accepted Date: Aug. 03, 2024
Rev Recd Date: Jul. 18, 2024
Publish Date: Aug. 22, 2024

Abstract

Abstract

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [¹⁵N₂]-cystine and [¹³C₅]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.
- UDCA,
- SLC7A11,
- Cystine,
- GSH,
- Oxidative stress,
- RLPS

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References(50)

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