IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3
BackgroundCyclic GMP-AMP synthase (cGAS)-stimulator-of-interferon genes (STING) pathway is a cytosolic DNA sensor system. The production of this pathway, interferon-β (IFNβ), could suppress the growth of tumor cells, yet it is unclear whether ferroptosis is involved in IFNβ-induced cell death.Method...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1535554/full |
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| author | Huiyue Dong Huiyue Dong Ling Zhu Ling Zhu Jingjing Sun Jingjing Sun Qiuyan Chen Qiuyan Chen Pengyang Liu Pengyang Liu Wei Zhang Huajing Zeng Rong Lin Rong Lin Zongyang Yu Zongyang Yu Jun Lu Jun Lu Jun Lu Jun Lu |
| author_facet | Huiyue Dong Huiyue Dong Ling Zhu Ling Zhu Jingjing Sun Jingjing Sun Qiuyan Chen Qiuyan Chen Pengyang Liu Pengyang Liu Wei Zhang Huajing Zeng Rong Lin Rong Lin Zongyang Yu Zongyang Yu Jun Lu Jun Lu Jun Lu Jun Lu |
| author_sort | Huiyue Dong |
| collection | DOAJ |
| description | BackgroundCyclic GMP-AMP synthase (cGAS)-stimulator-of-interferon genes (STING) pathway is a cytosolic DNA sensor system. The production of this pathway, interferon-β (IFNβ), could suppress the growth of tumor cells, yet it is unclear whether ferroptosis is involved in IFNβ-induced cell death.MethodsThe effects of IFNβ on ferroptosis were analyzed in HT1080, 4T1, HCT116 and 786-O cells. HT1080 and 4T1 cells treated with IFNβ were subjected to RNA-Seq analysis. STAT1, STAT3, TRIM21, and TRIM22 were silenced by siRNAs to examine their effects on IFNβ-induced ferroptosis. The cGAS-STING signaling pathway-activated mice were used to evaluate the effects of IFNβ on ferroptosis in vivo. HT1080 cells, three-dimensional (3D) spheroids, and the xenograft mouse models were treated with IFNβ, RSL3, or IFNβ combination with RSL3 to analyze whether IFNβ enhances RSL3-induced ferroptosis.ResultsHere, we found that IFNβ could promote intracellular Fe2+ and lipid peroxidation levels, and decrease GSH levels in tumor cells. RNA sequencing data revealed that IFNβ induced a transcriptomic disturbance in ferroptosis-related genes. Knockdown of tripartite motif-containing 22 (TRIM22) suppressed the levels of intracellular Fe2+ and lipid ROS. It also reduced heme oxygenase (HMOX1) protein levels and increased ferroptosis suppressor protein 1 (FSP1) levels in HT1080 cells treated with IFNβ. Furthermore, our results illustrated that IFNβ enhanced the RAS-selective lethal 3 (RSL3)-induced ferroptosis and the inhibitory effect of RSL3 on GPX4. Meanwhile, compared to the groups treated with either IFNβ or RSL3 alone, the combination treatment of IFNβ and RSL3 significantly inhibited the growth of HT1080 three-dimensional (3D) spheroids and tumor in a mouse xenograft model.ConclusionsOur work reveals a role for IFNβ in promoting ferroptosis and provides evidence that IFNβ could be used with RSL3 to increase cytotoxic effects in tumor cells. |
| format | Article |
| id | doaj-art-d16b998495254fca8855fa254b2ee4ba |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-d16b998495254fca8855fa254b2ee4ba2025-02-05T07:32:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15355541535554IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3Huiyue Dong0Huiyue Dong1Ling Zhu2Ling Zhu3Jingjing Sun4Jingjing Sun5Qiuyan Chen6Qiuyan Chen7Pengyang Liu8Pengyang Liu9Wei Zhang10Huajing Zeng11Rong Lin12Rong Lin13Zongyang Yu14Zongyang Yu15Jun Lu16Jun Lu17Jun Lu18Jun Lu19Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (the 900th Hospital of Joint Logistic Support Force), Xiamen University, Fuzhou, ChinaLaboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (the 900th Hospital of Joint Logistic Support Force), Xiamen University, Fuzhou, ChinaLaboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (the 900th Hospital of Joint Logistic Support Force), Xiamen University, Fuzhou, ChinaClinical Laboratory, Wuhan Children’s Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, ChinaFujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (the 900th Hospital of Joint Logistic Support Force), Xiamen University, Fuzhou, ChinaLaboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (the 900th Hospital of Joint Logistic Support Force), Xiamen University, Fuzhou, ChinaLaboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFuzong Teaching Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaLaboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (the 900th Hospital of Joint Logistic Support Force), Xiamen University, Fuzhou, ChinaLaboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFuzong Teaching Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaDepartment of Pulmonary and Critical Care Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (the 900th Hospital of Joint Logistic Support Force), Xiamen University, Fuzhou, ChinaLaboratory of Basic Medicine, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, ChinaFuzong Teaching Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaOrgan transplant institute, Dongfang Hospital, Xiamen University, Fuzhou, ChinaBackgroundCyclic GMP-AMP synthase (cGAS)-stimulator-of-interferon genes (STING) pathway is a cytosolic DNA sensor system. The production of this pathway, interferon-β (IFNβ), could suppress the growth of tumor cells, yet it is unclear whether ferroptosis is involved in IFNβ-induced cell death.MethodsThe effects of IFNβ on ferroptosis were analyzed in HT1080, 4T1, HCT116 and 786-O cells. HT1080 and 4T1 cells treated with IFNβ were subjected to RNA-Seq analysis. STAT1, STAT3, TRIM21, and TRIM22 were silenced by siRNAs to examine their effects on IFNβ-induced ferroptosis. The cGAS-STING signaling pathway-activated mice were used to evaluate the effects of IFNβ on ferroptosis in vivo. HT1080 cells, three-dimensional (3D) spheroids, and the xenograft mouse models were treated with IFNβ, RSL3, or IFNβ combination with RSL3 to analyze whether IFNβ enhances RSL3-induced ferroptosis.ResultsHere, we found that IFNβ could promote intracellular Fe2+ and lipid peroxidation levels, and decrease GSH levels in tumor cells. RNA sequencing data revealed that IFNβ induced a transcriptomic disturbance in ferroptosis-related genes. Knockdown of tripartite motif-containing 22 (TRIM22) suppressed the levels of intracellular Fe2+ and lipid ROS. It also reduced heme oxygenase (HMOX1) protein levels and increased ferroptosis suppressor protein 1 (FSP1) levels in HT1080 cells treated with IFNβ. Furthermore, our results illustrated that IFNβ enhanced the RAS-selective lethal 3 (RSL3)-induced ferroptosis and the inhibitory effect of RSL3 on GPX4. Meanwhile, compared to the groups treated with either IFNβ or RSL3 alone, the combination treatment of IFNβ and RSL3 significantly inhibited the growth of HT1080 three-dimensional (3D) spheroids and tumor in a mouse xenograft model.ConclusionsOur work reveals a role for IFNβ in promoting ferroptosis and provides evidence that IFNβ could be used with RSL3 to increase cytotoxic effects in tumor cells.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1535554/fullIFNβferroptosiscGAS-STINGTRIM22RSL3 |
| spellingShingle | Huiyue Dong Huiyue Dong Ling Zhu Ling Zhu Jingjing Sun Jingjing Sun Qiuyan Chen Qiuyan Chen Pengyang Liu Pengyang Liu Wei Zhang Huajing Zeng Rong Lin Rong Lin Zongyang Yu Zongyang Yu Jun Lu Jun Lu Jun Lu Jun Lu IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3 Frontiers in Immunology IFNβ ferroptosis cGAS-STING TRIM22 RSL3 |
| title | IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3 |
| title_full | IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3 |
| title_fullStr | IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3 |
| title_full_unstemmed | IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3 |
| title_short | IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3 |
| title_sort | ifnβ drives ferroptosis through elevating trim22 and promotes the cytotoxicity of rsl3 |
| topic | IFNβ ferroptosis cGAS-STING TRIM22 RSL3 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1535554/full |
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