Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron- dependent manner

• 成果类型: Article
• 署名作者: Qian, Xu; Zhou, Qimin; Ouyang, Yuan; Wu, Xiaohong; Sun, Xue; Wang, Shuo; Duan, Yuran; Hu, Zhiqiang; Hou, Yueru; Wang, Zheng; Chen, Xiaohan; Wang, Katherine L.; Shen, Yuli; Dong, Bofei; Lin, Yanni; Wen, Ting; Tian, Qi; Guo, Zhanpeng; Li, Min; Xiao, Liwei; Wu, Qingang; Meng, Ying; Liu, Guijun; Ying, Hangjie; Zhou, Yahui; Zhang, Wuchang; Duan, Shengzhong; Bai, Xueli; Liu, Tong; Zhan, Peng; Lu, Zhimin; Xu, Daqian
• 署名单位: Zhejiang Cancer Hospital; Chinese Academy of Sciences; Hangzhou Institute of Medicine, CAS; Zhejiang University; Zhejiang University; Zhejiang University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Harbin Medical University; Harbin Medical University; Shandong University; Zhejiang University; Harbin Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14820
• DOI: 10.1073/pnas.241247312
• 发表日期: 2025-02-04
• 关键词: activated receptor-alpha; regulatory proteins; cancer; ampk; phosphorylation; metabolism; PATHWAY; transcription; acetylation; homeostasis

摘要

Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeo-stasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carci-noma (HCC) cells induced AMPK- dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin alpha 7 and subsequent nuclear translocation. Nucleus- translocated Transferrin interacts with PPAR alpha and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPAR alpha- associated Transferrin upregulates iron- dependent PHD2- mediated PPAR alpha P87 hydroxylation and subsequently dis-rupts the binding of MDM2 to PPAR alpha, therefore inhibiting MDM2- mediated PPAR alpha ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS muta-tion or knock- in expression of PPAR alpha P87A inhibited PPAR alpha- mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK- Transferrin- PPAR alpha axis could synergize with a well- established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPAR alpha P87 hydroxylation is positively correlated with PPAR alpha expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPAR alpha through iron- dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.