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ResearchIn-Press PreviewCell biologyGastroenterologyHepatology Open Access | 10.1172/JCI195685

Chronic stress-induced ANPEP drives liver cancer progression by increasing glutathione synthesis and inhibiting ferroptosis

Yongkang Wu,1 Yankun Zhang,1 Xiaojia Shi,1 Mengting Wu,1 Min Sun,1 Ying Feng,1 Wenmeng Ma,1 Xiule Jiang,1 Dingqi Fei,1 Mingjian Zhao,1 Zhuanchang Wu,2 Chunyang Li,3 Xiaohong Liang,2 Lifen Gao,2 Chunhong Ma,2 and Xuetian Yue1

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

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1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

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1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

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1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Wu, M. in: PubMed | Google Scholar

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

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1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Feng, Y. in: PubMed | Google Scholar

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Ma, W. in: PubMed | Google Scholar

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Jiang, X. in: PubMed | Google Scholar

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

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1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

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1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Wu, Z. in: PubMed | Google Scholar |

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Li, C. in: PubMed | Google Scholar |

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Liang, X. in: PubMed | Google Scholar |

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Gao, L. in: PubMed | Google Scholar |

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Ma, C. in: PubMed | Google Scholar

1Department of Cellular Biology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

2Key Laboratory for Experimental Teratology of Ministry of Education and Dep, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

3Key Laboratory for Experimental Teratology of the Ministry of Education, De, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China

Find articles by Yue, X. in: PubMed | Google Scholar |

Published December 2, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI195685.
Copyright © 2025, Wu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 2, 2025 - Version history
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Abstract

Emerging evidence demonstrates that chronic stress alters immunological, neurochemical and endocrinological functions, thereby promoting tumor progression. However, the underlying metabolic mechanism of chronic stress in tumor progression is still elusive. Using multi-omics analysis, we found that aminopeptidase N (ANPEP) was upregulated in tumors with chronic restraint, associating with the reprogramming of amino acid metabolism. Functional assays revealed that ANPEP promoted liver cancer growth and metastasis. Knockdown of ANPEP blocked chronic stress-induced liver cancer progression. Chronic stress-induced glucocorticoids promoted nuclear receptor subfamily 3 group C member 1 (NR3C1) nuclear translocation to activate ANPEP transcription by directly binding to its promoter. Furthermore, ANPEP promotes glutathione synthesis, subsequently inhibiting reactive oxygen species (ROS)-induced ferroptosis. Mechanistically, ANPEP interacted with solute carrier family 3 member 2 (SLC3A2) to block membrane associated ring-CH-type finger 8-mediated (MARCH8-mediated) lysosome-dependent degradation of SLC3A2, promoting intracellular L-cystine transport, thereby increasing glutathione synthesis. The combination of ANPEP silencing and sorafenib treatment showed a synergistic effect in inhibiting liver cancer progression. Finally, clinical data and mouse models demonstrated that chronic stress drove liver tumor progression via ANPEP-regulated SLC3A2. These findings reveal unanticipated communication between chronic stress and metabolic reprogramming during liver cancer progression, providing potential therapeutic implications for liver cancer.

Graphical Abstract
graphical abstract
Supplemental material

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View Supplemental Table 1 Identification of metabolites in serum with positive ion patterns.

View Supplemental Table 2 Identification of metabolites in serum whit negative ion patterns.

View Supplemental Table 3 Identification of metabolites in orthotopic liver tumors with positive ion patterns.

View Supplemental Table 4 Identification of metabolites in orthotopic liver tumors with negative ion patterns

View Supplemental Table 5 Significantly enriched metabolic pathways in orthotopic liver tumors and serum samples.

View Supplemental Table 6 Differential expressed genes between chronic stress-treated mouse tumors and their control.

View Supplemental Table 7 Sequence of primers, siRNAs, shRNAs and probes.

View Supplemental Table 8 List of antibodies used in this manuscript.

View Supplemental Table 9 Patients inforamtion of HCC tissue microarray.

View Supplemental Table 10 List of genes for chronic stress gene signature.

Version history
  • Version 1 (December 2, 2025): In-Press Preview
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