Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis
Enterococcus faecalis-infected macrophages produce 4-hydroxynonenal (4-HNE) that mediates microbiota-induced bystander effect (MIBE) leading to colorectal cancer (CRC). Glutathione S-transferase alpha 4 (Gsta4), a specific detoxifying enzyme for 4-HNE, is overexpressed in human CRC and E. faecalis-i...
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Taylor & Francis Group
2025-12-01
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| Series: | Gut Microbes |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19490976.2025.2451090 |
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| author | Yuanyuan Ju Chunhua Ma Lin Huang Yumei Tao Tianqi Li Haibo Li Mark M. Huycke Yonghong Yang Xingmin Wang |
| author_facet | Yuanyuan Ju Chunhua Ma Lin Huang Yumei Tao Tianqi Li Haibo Li Mark M. Huycke Yonghong Yang Xingmin Wang |
| author_sort | Yuanyuan Ju |
| collection | DOAJ |
| description | Enterococcus faecalis-infected macrophages produce 4-hydroxynonenal (4-HNE) that mediates microbiota-induced bystander effect (MIBE) leading to colorectal cancer (CRC). Glutathione S-transferase alpha 4 (Gsta4), a specific detoxifying enzyme for 4-HNE, is overexpressed in human CRC and E. faecalis-induced murine CRC. However, the roles of Gsta4 in E. faecalis-induced colitis and CRC remain unclear. Herein, we demonstrate that Gsta4 is essential for MIBE by protecting macrophages from E. faecalis-induced ferroptosis. E. faecalis OG1RFSS was used to induce colitis in Gsta4−/− and Il10−/−/Gsta4−/− mice by orogastric gavage. Ferroptosis was assessed in Gsta4-deficient murine macrophages. We found that, unlike Il10−/− mice, Gsta4−/− and Il10−/−/Gsta4−/− mice colonized with E. faecalis failed to develop colitis or CRC. Immunofluorescent staining showed a reduction of macrophages in the lamina propria of E. faecalis-colonized Il10−/−/Gsta4−/− mice, as well as decreased Gpx4 expression, indicating the occurrence of ferroptosis. Ferroptosis was further confirmed in Gsta4-deficient murine macrophages infected with E. faecalis. Moreover, Gsta4 inactivation induced the upregulation of Hmox1 and phosphorylated c-Jun while blocked Nos2 expression, leading to the accumulation of intracellular ferrous iron, lipid peroxidation and, eventually, ferroptosis. Finally, Mapk8, as a ferroptosis driver, was remarkably elevated in E. faecalis-infected Gsta4-deficient macrophages. These results suggest that Gsta4 inactivation blocks MIBE by eliminating macrophages, thereby attenuates E. faecalis-induced colitis and CRC. |
| format | Article |
| id | doaj-art-e448c23daf3649f09da1e4a5f34a1f1a |
| institution | Kabale University |
| issn | 1949-0976 1949-0984 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Gut Microbes |
| spelling | doaj-art-e448c23daf3649f09da1e4a5f34a1f1a2025-01-17T02:29:00ZengTaylor & Francis GroupGut Microbes1949-09761949-09842025-12-0117110.1080/19490976.2025.2451090Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosisYuanyuan Ju0Chunhua Ma1Lin Huang2Yumei Tao3Tianqi Li4Haibo Li5Mark M. Huycke6Yonghong Yang7Xingmin Wang8Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, ChinaNantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Gastroenterology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Pathology, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, ChinaNantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, ChinaDepartment of Clinical Laboratory, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, ChinaStephenson Cancer Center, Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USADepartment of Nephrology, Rheumatology, and Immunology, Nantong Children’s Hospital, Nantong, Jiangsu, ChinaNantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, Jiangsu, ChinaEnterococcus faecalis-infected macrophages produce 4-hydroxynonenal (4-HNE) that mediates microbiota-induced bystander effect (MIBE) leading to colorectal cancer (CRC). Glutathione S-transferase alpha 4 (Gsta4), a specific detoxifying enzyme for 4-HNE, is overexpressed in human CRC and E. faecalis-induced murine CRC. However, the roles of Gsta4 in E. faecalis-induced colitis and CRC remain unclear. Herein, we demonstrate that Gsta4 is essential for MIBE by protecting macrophages from E. faecalis-induced ferroptosis. E. faecalis OG1RFSS was used to induce colitis in Gsta4−/− and Il10−/−/Gsta4−/− mice by orogastric gavage. Ferroptosis was assessed in Gsta4-deficient murine macrophages. We found that, unlike Il10−/− mice, Gsta4−/− and Il10−/−/Gsta4−/− mice colonized with E. faecalis failed to develop colitis or CRC. Immunofluorescent staining showed a reduction of macrophages in the lamina propria of E. faecalis-colonized Il10−/−/Gsta4−/− mice, as well as decreased Gpx4 expression, indicating the occurrence of ferroptosis. Ferroptosis was further confirmed in Gsta4-deficient murine macrophages infected with E. faecalis. Moreover, Gsta4 inactivation induced the upregulation of Hmox1 and phosphorylated c-Jun while blocked Nos2 expression, leading to the accumulation of intracellular ferrous iron, lipid peroxidation and, eventually, ferroptosis. Finally, Mapk8, as a ferroptosis driver, was remarkably elevated in E. faecalis-infected Gsta4-deficient macrophages. These results suggest that Gsta4 inactivation blocks MIBE by eliminating macrophages, thereby attenuates E. faecalis-induced colitis and CRC.https://www.tandfonline.com/doi/10.1080/19490976.2025.2451090Glutathione S-transferase alpha 4ferroptosisEnterococcus faecalismacrophagemicrobiota-induced bystander effectcolorectal cancer |
| spellingShingle | Yuanyuan Ju Chunhua Ma Lin Huang Yumei Tao Tianqi Li Haibo Li Mark M. Huycke Yonghong Yang Xingmin Wang Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis Gut Microbes Glutathione S-transferase alpha 4 ferroptosis Enterococcus faecalis macrophage microbiota-induced bystander effect colorectal cancer |
| title | Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis |
| title_full | Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis |
| title_fullStr | Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis |
| title_full_unstemmed | Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis |
| title_short | Inactivation of glutathione S-transferase alpha 4 blocks Enterococcus faecalis-induced bystander effect by promoting macrophage ferroptosis |
| title_sort | inactivation of glutathione s transferase alpha 4 blocks enterococcus faecalis induced bystander effect by promoting macrophage ferroptosis |
| topic | Glutathione S-transferase alpha 4 ferroptosis Enterococcus faecalis macrophage microbiota-induced bystander effect colorectal cancer |
| url | https://www.tandfonline.com/doi/10.1080/19490976.2025.2451090 |
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