journal article·2026-01Open access

Obesity‐Associated TRIM15 Promotes the Proliferation of Esophageal Adenocarcinoma Through the YY2/FOXRED1 Axis

Haohui Wang, Chong Yang, Dayuan Luo, Pingting Liu, Zhen Zeng, Weilin Peng, Dongzi Peng, Hao Su, Xiaoxiong Xiao, Haiqin Wang, Xin Jin

Advanced Science· Volume 13· Issue 4

Abstract

Abstract Obesity has been identified as an independent risk factor for gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma (EAC). Oxidative stress and inflammation driven by chronic GERD are the main causes of the tumorigenesis of EAC, but the underlying mechanism remains elusive. Here, the inflammation‐upregulated E3 ligase, tripartite motif 15 (TRIM15), is identified as a key driver of obesity‐associated EAC. TRIM15 promotes the degradation of YY2 is demonstrated through the ubiquitin‐proteasome system, which in turn dysregulates lipid metabolism and enhances the proliferation of EAC cells. Furthermore, YY2 transcriptionally is shown that increases FOXRED1 expression. FOXRED1 is subsequently identified as an essential effector for the TRIM15‐induced dysregulation of lipid and energy metabolism in EAC cells. Thus, a novel obesity‐associated TRIM15/YY2/FOXRED1 axis is identified that contributes to the proliferation of EAC. Given that lipid metabolism regulates ferroptosis by controlling cellular processes associated with phospholipid peroxidation. The TRIM15/YY2/FOXRED1 axis demonstrates that it modulates SLC3A2 expression via the mTOR/c‐MYC pathway, thereby regulating GPX4 levels to influence EAC sensitivity to ferroptosis‐inducing compounds and proposing a therapeutic strategy for EAC.
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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · interferon and immune responses · Cancer-related molecular mechanisms research

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

Affiliations

Department of Thoracic Surgery The Second Xiangya Hospital Central South University Changsha Hunan 410011 China

Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer The Second Xiangya Hospital Central South University Changsha Hunan 410011 China

Department of Hepatobiliary and Pancreatic Surgery Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu 610072 China

Department of Health Management Center Hunan Provincial Maternal and Child Health Care Hospital Changsha Hunan 410008 China

Department of Geriatrics The Second Xiangya Hospital Central South University Changsha Hunan 410011 China

Hunan Clinical Medical Research Center for Geriatric Syndrome Changsha Hunan 410011 China

Department of Gastroenterology The Second Xiangya Hospital Central South University Changsha Hunan 410011 China

Research Center of Digestive Disease Central South University Changsha Hunan 410011 China

Department of Urology The Second Xiangya Hospital Central South University Changsha Hunan 410011 China

Uro‐Oncology Institute of Central South University Changsha Hunan 410011 China

Furong Laboratory Central South University Changsha Hunan 410000 China

Department of Thoracic Surgery Xiangya Hospital Central South University Changsha Hunan 410008 China

Xiangya Lung Cancer Center Xiangya Hospital Central South University Changsha Hunan 410008 China

Funding

Natural Science Foundation of Hunan Province

References (76)

Show source-provided references
1. 10.1080/17474124.2020.176434810.1080/17474124.2020.1764348 ↗
2. 10.1016/j.redox.2021.10189410.1016/j.redox.2021.101894 ↗
3. 10.1056/NEJMsr160660210.1056/NEJMsr1606602 ↗
4. 10.1023/B:DDAS.0000037790.11724.7010.1023/B:DDAS.0000037790.11724.70 ↗
5. 10.1053/j.gastro.2010.03.03510.1053/j.gastro.2010.03.035 ↗
6. 10.1186/s40880-018-0301-410.1186/s40880-018-0301-4 ↗
7. 10.3390/ijms24151203210.3390/ijms241512032 ↗
8. 10.3390/metabo1009034510.3390/metabo10090345 ↗
9. 10.1038/s41568-021-00388-410.1038/s41568-021-00388-4 ↗
10. 10.1016/j.bbadis.2021.16621310.1016/j.bbadis.2021.166213 ↗
11. 10.1038/s41419-023-05577-710.1038/s41419-023-05577-7 ↗
12. 10.1016/j.cellsig.2021.11021010.1016/j.cellsig.2021.110210 ↗
13. 10.1016/j.bbadis.2024.16718310.1016/j.bbadis.2024.167183 ↗
14. 10.3390/cells906150510.3390/cells9061505 ↗
15. 10.1016/j.molcel.2022.03.02210.1016/j.molcel.2022.03.022 ↗
16. 10.1016/j.ccell.2023.05.00110.1016/j.ccell.2023.05.001 ↗
17. 10.3390/ijms2313747510.3390/ijms23137475 ↗
18. 10.1016/j.intimp.2022.10939510.1016/j.intimp.2022.109395 ↗
19. 10.1038/s41467-020-20434-310.1038/s41467-020-20434-3 ↗
20. Dodington D. W. · Histopathology · 2024
21. 10.1186/s40164-024-00529-z10.1186/s40164-024-00529-z ↗
22. 10.3390/ijms2511618810.3390/ijms25116188 ↗
23. 10.1016/j.tibs.2017.01.00210.1016/j.tibs.2017.01.002 ↗
24. 10.1002/advs.20210483610.1002/advs.202104836 ↗
25. 10.1002/advs.20220734910.1002/advs.202207349 ↗
26. 10.1111/jcmm.1591910.1111/jcmm.15919 ↗
27. 10.3389/fendo.2023.126717010.3389/fendo.2023.1267170 ↗
28. 10.1093/hmg/ddv05810.1093/hmg/ddv058 ↗
29. FEI W. · Am. J. Cancer Res. · 2016 · 6 · 2722
30. 10.1073/pnas.220943512010.1073/pnas.2209435120 ↗
31. 10.1007/s00204-015-1520-y10.1007/s00204-015-1520-y ↗
32. 10.3390/nu1510232310.3390/nu15102323 ↗
33. 10.3390/biom1204058010.3390/biom12040580 ↗
34. 10.1111/cge.1321510.1111/cge.13215 ↗
35. 10.1016/j.chembiol.2018.11.01610.1016/j.chembiol.2018.11.016 ↗
36. 10.1016/j.freeradbiomed.2023.03.01310.1016/j.freeradbiomed.2023.03.013 ↗
37. 10.1093/hmg/ddq41410.1093/hmg/ddq414 ↗
38. 10.1158/0008-5472.CAN-24-318010.1158/0008-5472.CAN-24-3180 ↗
39. 10.1002/advs.20240622010.1002/advs.202406220 ↗
40. 10.1172/JCI6426410.1172/JCI64264 ↗
41. Li L.‐D. · PLoS One · 2015 · 10
42. 10.1021/acsnano.4c0508410.1021/acsnano.4c05084 ↗
43. 10.1016/j.metabol.2018.11.00110.1016/j.metabol.2018.11.001 ↗
44. 10.1002/ctm2.81010.1002/ctm2.810 ↗
45. 10.1093/intimm/dxaa07810.1093/intimm/dxaa078 ↗
46. 10.1097/MED.0b013e3283444b0910.1097/MED.0b013e3283444b09 ↗
47. 10.1016/j.semcancer.2023.04.00310.1016/j.semcancer.2023.04.003 ↗
48. 10.3390/ijms2014346810.3390/ijms20143468 ↗
49. 10.1073/pnas.221647912010.1073/pnas.2216479120 ↗
50. 10.1016/j.celrep.2023.11343410.1016/j.celrep.2023.113434 ↗
51. 10.1097/CM9.000000000000360610.1097/CM9.0000000000003606 ↗
52. 10.1016/j.jaip.2024.12.02210.1016/j.jaip.2024.12.022 ↗
53. 10.1002/cam4.747210.1002/cam4.7472 ↗
54. 10.1002/hep.2897110.1002/hep.28971 ↗
55. 10.3390/ijms2316943810.3390/ijms23169438 ↗
56. 10.1016/j.cmet.2021.05.01910.1016/j.cmet.2021.05.019 ↗
57. 10.1002/hep.3252610.1002/hep.32526 ↗
58. 10.1007/s13577-022-00820-310.1007/s13577-022-00820-3 ↗
59. 10.1016/j.jlr.2023.10038210.1016/j.jlr.2023.100382 ↗
60. 10.1172/JCI16614910.1172/JCI166149 ↗
61. 10.1016/j.cell.2011.02.01310.1016/j.cell.2011.02.013 ↗
62. 10.3389/fcell.2024.139906510.3389/fcell.2024.1399065 ↗
63. 10.3390/healthcare1204041610.3390/healthcare12040416 ↗
64. 10.1007/s10863-021-09872-w10.1007/s10863-021-09872-w ↗
65. 10.1186/s12964-022-00875-710.1186/s12964-022-00875-7 ↗
66. 10.12659/MSM.91114210.12659/MSM.911142 ↗
67. 10.3389/fphar.2020.0023910.3389/fphar.2020.00239 ↗
68. 10.1016/j.ceb.2017.11.00110.1016/j.ceb.2017.11.001 ↗
69. 10.1007/s00424010053710.1007/s004240100537 ↗
70. 10.1016/j.phymed.2023.15475610.1016/j.phymed.2023.154756 ↗
71. 10.3390/ijms2401044910.3390/ijms24010449 ↗
72. 10.3389/fphar.2022.91029210.3389/fphar.2022.910292 ↗
73. 10.1016/j.biopha.2023.11611210.1016/j.biopha.2023.116112 ↗
74. Chen H. · Antioxidants · 2022 · 11
75. 10.1155/2020/676547410.1155/2020/6765474 ↗
76. 10.1093/nar/gkae97310.1093/nar/gkae973 ↗