biostudies-literatureQian XMinistry of Science and Technology of the People's Republic of China (MOST)Ministry of Science and Technology of the People's Republic of ChinaZhejiang University (ZJU)MOST | National Natural Science Foundation of China (NSFC)MOST | NSFC | NSFC-Zhejiang Joint Fund | Natural Science Foundation of Zhejiang ProvinceMOST | NSFC | NSFC-Zhejiang Joint Fund | Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health TalentsShanghai Municipal Human Resources and Social Security BureauMOST | National Natural Science Foundation of ChinaZhejiang UniversityMOST | NSFC | NSFC-Zhejiang Joint Fund | Natural Science Foundation of Zhejiang Province (ZJNSF)e2412473122https://www.ebi.ac.uk/biostudies/studies/S-EPMC11804496biostudies-literatureUnknown122(5)Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequeProceedings of the National Academy of Sciences of the United States of AmericaTransferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner.PMC1180449682072630921571132020YFA08033002022R010068210365882272406No.2022PJD040LQ22H1600232021YFA0805600188020*194221901/02982173114LD21H160003823728142019YFA090580082188102LD22H16000282030074Guo ZHu ZWu QLu ZLin YYing HLiu THou YWen TMeng YZhan PWang SChen XShen YWang ZWu XDong BZhou QXu DSun XZhou YBai XLi MQian XZhang WXiao LDuan SOuyang YDuan YWang KLTian QLiu GfalseTransferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner.Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subseque2025-01-01T00:00:00Z2025 Feb2026-03-18T14:04:43.625Z2025-08-23T03:07:25.402ZS-EPMC118044963988891710.1073/pnas.2412473122