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Methionine depletion inhibits hepatocellular carcinoma by inducing ferroptosis and suppressing epithelial-mesenchymal transition through the ARNT2/UBE2Z pathway
Dong-Dong Yin, Wei-Yu Jiang, Yu-Ting Huang, Shu-Ping Zhou, Yin-Ci Zhang, Department of Pathology, The First Hospital of Anhui University of Science and Technology, Huainan 232000, Anhui Province, China
Co-corresponding authors: Shu-Ping Zhou and Yin-Ci Zhang.
Author contributions: Yin DD and Zhang YC wrote the main manuscript text; Yin DD, Jiang WY, Huang YT, Zhou SP and Zhang YC prepared figures, tables; Zhou SP and Zhang YC have played important and indispensable roles in the manuscript preparation as the co-corresponding authors; all authors reviewed the manuscript; final manuscript read and approved by all authors.
Supported by Health Research Program of Anhui, No. AHWJ2023A30019; Clinical and Translational Research Project of Anhui Province, No. 202527c10020090 and No. 202304295107020036; and University-Industry Collaborative Education Program, No. 230907010211931.
Institutional review board statement: The study was reviewed by the Ethics Committee of the First Hospital of Anhui University of Science and Technology (No. 2023-KY-AHSWJW005-001).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
Corresponding author: Yin-Ci Zhang, Department of Pathology, The First Hospital of Anhui University of Science and Technology, No. 203 Huaibin Road, Tianjia’an District, Huainan 232000, Anhui Province, China. 13345543605@163.com
Received: February 27, 2026
Revised: April 4, 2026
Accepted: May 11, 2026
Published online: June 27, 2026
Processing time: 115 Days and 13.5 Hours
Revised: April 4, 2026
Accepted: May 11, 2026
Published online: June 27, 2026
Processing time: 115 Days and 13.5 Hours
Core Tip
Core Tip: Aberrant methionine (Met) metabolism critically promotes the progression of hepatocellular carcinoma (HCC). Met deficiency may induce ferroptosis and inhibit epithelial-mesenchymal transition through the ARNT2/UBE2Z axis, thereby suppressing HCC progression, whereas Met supplementation reverses these effects. Furthermore, high expression levels of ARNT2 and UBE2Z predict unfavorable prognosis in HCC patients. Collectively, these findings indicate that the Met-ARNT2/UBE2Z pathway may serve as a novel anti-HCC therapeutic target.