journal article·2025-05Open access

ISG15 Enhances the Activity of γ‐Glutamate Cysteine Ligase to Suppress Apoptosis in High Fat Diet‐Promoted Hepatocellular Carcinoma

Xinran Liu, Qiujin Ma, Zhao Jia, Yihao Zhou, Churong Zou, Yushuo Xiao, Yuchen Chen, Chuyao Ma, Liangliang Song, Jing Yang, Chen Wang, Huidie Xu, Hong Chen, Jiajian Shi, Junqiu Yue, Yu Sun, Desheng Hu, Robert B Petersen, Yangkai Li, Anlin Peng, Kun Huang, Ling Zheng

Advanced Science· Volume 12· Issue 19

Abstract

Abstract Obesity is a leading risk factor for development of hepatocellular carcinoma (HCC). High‐fat intake produces cytotoxic effects in liver cells, such as excessive reactive oxygen species (ROS) accumulation and apoptosis. How HCC cells regulate ROS level and escape the cytotoxic effects of high fat diet (HFD) stress remains unclear. Herein, this work reports a critical anti‐ROS/apoptotic role of the ubiquitin‐like protein interferon stimulated gene 15 (ISG15) in HFD‐promoted HCC. In mouse models and clinical HCC samples, upregulation of ISG15 is associated with hepatic steatosis. Notably, upregulated ISG15 elevates cellular glutathione levels, which subsequently reduces ROS accumulation and confers resistance to apoptosis in HCC cells. In diethylnitrosamine‐induced HCC mouse model, HFD‐feeding promotes HCC progression in wildtype mice, while tumor growth is significantly suppressed accompanied by apoptosis of HCC cells in Isg15‐KO mice. Mechanistically, ISG15 promotes the activity of γ‐glutamate cysteine ligase (γ‐GCL), a rate‐limiting heterodimeric holoenzyme of glutathione synthesis consisting of glutamate‐cysteine ligase catalytic subunit (GCLC) and glutamate‐cysteine ligase modifier subunit (GCLM). Independent of ISGylation, ISG15 forms an ISG15/GCLM/GCLC complex that promotes GCLM‐GCLC interaction, increases glutathione generation and inhibits HFD‐induced apoptosis in HCC cells. Together, an anti‐apoptotic ISG15‐γ‐GCL‐glutothione axis is suggested in HFD‐promoted HCC.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: interferon and immune responses · Ferroptosis and cancer prognosis · Immune cells in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Pharmacy Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science & Technology Wuhan 430030 China

State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences; Frontier Science Center for Immunology and Metabolism, College of Life Sciences Wuhan University Wuhan 430072 China

Department of Pathology Hubei Cancer Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430079 China

Department of Integrated Traditional Chinese and Western Medicine Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 China

China‐Russia Medical Research Center for Stress Immunology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430000 China

Foundational Sciences Central Michigan University College of Medicine Mt. Pleasant MI 48859 USA

Department of Thoracic Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Department of Pharmacy The Third Hospital of Wuhan Tongren Hospital of Wuhan University Wuhan 430070 China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China · Natural Science Foundation of Hubei Province

References (58)

Show source-provided references
1. 10.3322/caac.2166010.3322/caac.21660 ↗
2. 10.1002/hep.3128810.1002/hep.31288 ↗
3. 10.1002/hep.3181110.1002/hep.31811 ↗
4. 10.1097/HEP.000000000000000510.1097/HEP.0000000000000005 ↗
5. 10.1016/j.cell.2009.12.05210.1016/j.cell.2009.12.052 ↗
6. 10.1016/j.jhep.2019.08.01410.1016/j.jhep.2019.08.014 ↗
7. 10.1016/j.jhep.2022.06.01210.1016/j.jhep.2022.06.012 ↗
8. 10.1016/j.jhep.2020.03.05010.1016/j.jhep.2020.03.050 ↗
9. 10.1038/s41568-021-00435-010.1038/s41568-021-00435-0 ↗
10. 10.1016/j.ejphar.2023.17549710.1016/j.ejphar.2023.175497 ↗
11. 10.1016/j.ejphar.2023.17574410.1016/j.ejphar.2023.175744 ↗
12. 10.1016/j.lfs.2023.12168810.1016/j.lfs.2023.121688 ↗
13. 10.1016/j.cell.2017.05.04610.1016/j.cell.2017.05.046 ↗
14. 10.1016/j.copbio.2021.03.00110.1016/j.copbio.2021.03.001 ↗
15. 10.1016/j.mam.2008.08.00910.1016/j.mam.2008.08.009 ↗
16. 10.1038/nature1380110.1038/nature13801 ↗
17. 10.1038/s12276-022-00872-310.1038/s12276-022-00872-3 ↗
18. 10.1016/j.molcel.2017.10.00310.1016/j.molcel.2017.10.003 ↗
19. 10.1007/s00262-019-02422-910.1007/s00262-019-02422-9 ↗
20. 10.1172/JCI6176210.1172/JCI61762 ↗
21. 10.18632/oncotarget.231610.18632/oncotarget.2316 ↗
22. 10.1016/j.canlet.2023.21608010.1016/j.canlet.2023.216080 ↗
23. Sorenson E. C. · PLoS One · 1210.1371/journal.pone.0176562 ↗
24. 10.34133/research.003610.34133/research.0036 ↗
25. 10.15252/embr.20225612810.15252/embr.202256128 ↗
26. 10.2337/db20-043710.2337/db20-0437 ↗
27. 10.1038/s41598-019-48746-510.1038/s41598-019-48746-5 ↗
28. 10.1002/hep.2675110.1002/hep.26751 ↗
29. 10.3390/ijms2301057710.3390/ijms23010577 ↗
30. 10.1002/hep4.144110.1002/hep4.1441 ↗
31. 10.2174/156652401666616031615214710.2174/1566524016666160316152147 ↗
32. 10.1126/scitranslmed.abo447410.1126/scitranslmed.abo4474 ↗
33. 10.1080/0360253070146851610.1080/03602530701468516 ↗
34. 10.1038/nature1018910.1038/nature10189 ↗
35. 10.1016/j.canlet.2018.06.02810.1016/j.canlet.2018.06.028 ↗
36. 10.1016/S0021-9258(18)35980-510.1016/S0021-9258(18)35980-5 ↗
37. 10.1074/jbc.M110.11621010.1074/jbc.M110.116210 ↗
38. 10.1038/s41467-021-27838-910.1038/s41467-021-27838-9 ↗
39. 10.3390/vaccines902016410.3390/vaccines9020164 ↗
40. 10.1158/0008-5472.CAN-09-121210.1158/0008-5472.CAN-09-1212 ↗
41. 10.7150/jca.2976910.7150/jca.29769 ↗
42. 10.3389/fonc.2022.104089210.3389/fonc.2022.1040892 ↗
43. 10.1155/2013/97291310.1155/2013/972913 ↗
44. 10.1038/nrc396710.1038/nrc3967 ↗
45. 10.1002/advs.20220509110.1002/advs.202205091 ↗
46. 10.1016/j.jhep.2020.09.03710.1016/j.jhep.2020.09.037 ↗
47. 10.1158/2159-8290.CD-21-092210.1158/2159-8290.CD-21-0922 ↗
48. 10.1111/cas.1533610.1111/cas.15336 ↗
49. 10.1002/hep.2920210.1002/hep.29202 ↗
50. 10.1111/cas.1379410.1111/cas.13794 ↗
51. 10.1038/s41467-023-39713-w10.1038/s41467-023-39713-w ↗
52. 10.1038/s41467-017-02355-w10.1038/s41467-017-02355-w ↗
53. 10.1038/s41419-018-0555-410.1038/s41419-018-0555-4 ↗
54. 10.7150/thno.8430810.7150/thno.84308 ↗
55. 10.1038/s41467-022-31476-010.1038/s41467-022-31476-0 ↗
56. 10.1158/0008-5472.CAN-14-127910.1158/0008-5472.CAN-14-1279 ↗
57. 10.1073/pnas.230628812010.1073/pnas.2306288120 ↗
58. 10.1038/s41467-023-40036-z10.1038/s41467-023-40036-z ↗