Yin DD, Jiang WY, Huang YT, Zhou SP, Zhang YC. Methionine depletion inhibits hepatocellular carcinoma by inducing ferroptosis and suppressing epithelial-mesenchymal transition through the ARNT2/UBE2Z pathway. World J Hepatol 2026; 18(6): 120427 [DOI: 10.4254/wjh.120427]
Corresponding Author of This Article
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
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
research-article
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World J Hepatol. Jun 27, 2026; 18(6): 120427 Published online Jun 27, 2026. doi: 10.4254/wjh.120427
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
Abstract
BACKGROUND
Aberrant methionine (Met) metabolism, ferroptosis, and epithelial-mesenchymal transition (EMT) have been recognized as critical drivers of tumor progression. However, their crosstalk and underlying regulatory mechanisms in hepatocellular carcinoma (HCC) remain unclear.
AIM
To explore the effect of Met metabolic dysregulation on ferroptosis and EMT within HCC cells and its underlying mechanisms.
METHODS
Met levels in HCC cells were measured, and alterations in ferroptosis- and EMT-related markers were evaluated following Met depletion or supplementation. ARNT2 levels were assessed under altered Met conditions. ARNT2’s expression pattern in HCC tissues and its correlation with patient prognosis was analyzed by bioinformatics tools. The expression of ferroptosis/EMT markers and UBE2Z were examined after ARNT2 knockdown. UBE2Z levels in HCC tissues were measured and correlated with clinical outcomes.
RESULTS
The results demonstrated that, with prolonged culture duration, Met levels in HCC cells decreased more markedly compared to normal hepatocytes. Met depletion induced ferroptosis, inhibited EMT, and downregulated ARNT2 expression, whereas Met supplementation exerted opposite effects. Moreover, high ARNT2 expression within HCC tissues was closely related to unfavorable patient survival. ARNT2 knockdown enhanced expression of pro-ferroptotic markers, suppressed EMT, and reduced UBE2Z expression. UBE2Z up-regulation within HCC tissues was related to poor prognosis.
CONCLUSION
Met deficiency inhibits HCC progression by inducing ferroptosis and suppressing EMT via the ARNT2/UBE2Z signaling, while Met supplementation exerts the opposite effect.
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.
