Xie Fu'an, Niu Yujia, Chen Xiaobing, Kong Xu, Yan Guangting, Zhuang Aobo, Li Xi, Lian Lanlan, Qin Dongmei, Zhang Quan, Zhang Ruyi, Yang Kunrong, Xia Xiaogang, Chen Kun, Xiao Mengmeng, Yang Chunkang, Wu Ting, Shen Ye, Yu Chundong, Luo Chenghua, Lin Shu-Hai, Li Wengang
Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
J Pharm Anal. 2025 Jan;15(1):101068. doi: 10.1016/j.jpha.2024.101068. Epub 2024 Aug 22.
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. [N]-cystine and [C]-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.
熊去氧胆酸（UDCA）是人体内一种天然存在、低毒性且亲水性的胆汁酸（BA），由肠道菌群利用初级胆汁酸转化而来。溶质载体家族7成员11（SLC7A11）的功能是摄取细胞外胱氨酸以交换谷氨酸，并且在多种人类癌症中高表达。腹膜后脂肪肉瘤（RLPS）是指起源于腹膜后区域的脂肪肉瘤。脂质组学分析显示，与健康受试者相比，UDCA是RLPS患者血清中下调最显著的代谢物之一。UDCA浓度增加（≥25μg/mL）对脂肪肉瘤细胞的增殖具有抑制作用。[N]-胱氨酸和[C]-谷氨酰胺同位素示踪表明，UDCA会损害胱氨酸摄取和谷胱甘肽（GSH）合成。机制上，UDCA与胱氨酸转运体SLC7A11结合，抑制胱氨酸摄取并损害GSH的从头合成，导致活性氧（ROS）积累和线粒体氧化损伤。此外，UDCA可以增强铁死亡诱导剂（艾拉司群、RSL3）、小鼠双微体2（MDM2）抑制剂（Nutlin 3a、RG7112）、细胞周期蛋白依赖性激酶4（CDK4）抑制剂（阿贝西利）和谷氨酰胺酶抑制剂（CB839）的抗癌作用。总之，UDCA作为一种胱氨酸交换因子，与SLC7A11结合发挥抗肿瘤活性，SLC7A11不仅是胆汁酸的一种新转运体，也是UDCA的一个临床适用靶点。更重要的是，与其他抗肿瘤化疗或物理治疗联合使用时，UDCA可能以ROS依赖的方式为RLPS或其他类型的肿瘤提供有效且有前景的治疗策略。
