Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis
Abstract Background Sirolimus, the therapy choice for lymphangioleiomyomatosis (LAM), displayed cytostatic but not cytocidal action, with disease recurrence after withdrawal. The aim of this study is to identify novel potential biomarkers and therapeutic strategies for LAM patients. Methods TMT-labe...
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BMC
2025-05-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03285-8 |
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| author | Wenxue Bai Shengding Zhang Lijuan Hua Dongyuan Wang Mengyao Guo Xuezhao Wang Ying Zhou Yong Cao Qi Wang Ni Zhang Bin Xue Min Xie |
| author_facet | Wenxue Bai Shengding Zhang Lijuan Hua Dongyuan Wang Mengyao Guo Xuezhao Wang Ying Zhou Yong Cao Qi Wang Ni Zhang Bin Xue Min Xie |
| author_sort | Wenxue Bai |
| collection | DOAJ |
| description | Abstract Background Sirolimus, the therapy choice for lymphangioleiomyomatosis (LAM), displayed cytostatic but not cytocidal action, with disease recurrence after withdrawal. The aim of this study is to identify novel potential biomarkers and therapeutic strategies for LAM patients. Methods TMT-labeling proteomics was utilized for screening the differentially expressed proteins (DEPs) in the plasma of 10 LAM patients and 6 controls. Plasma levels of transferrin (TRF), ferritin (FRT) and beta2-microglobulin (B2M) were validated in a cohort of 30 LAM patients and 20 controls. The diagnostic efficacy of TRF with/without VEGF-D was assessed using ROC curve analysis. The therapeutic effects of a ferroptosis inducer artesunate (ART) were evaluated both in vitro Tsc2 − / − MEFs cells and in xenograft LAM models. Results Proteomics analysis revealed 132 DEPs between LAM patients and controls, which primarily enriched in the regulation of iron ion transport. LAM patients had decreased TRF, elevated FRT and B2M levels compared with controls in the confirmation cohort (p = 0.0386, p = 0.0327 and p = 0.0155, respectively) which independent with VEGF-D level or rapamycin therapy. TRF positively correlated with both FEV1% predicted (r = 0.4486, p = 0.0251) and DLCO% predicted (r = 0.4018, p = 0.0516) of LAM patients. The combination of TRF and VEGF-D showed superior diagnostic value compared to individual indicator. ART induced the ferroptosis and inhibited the growth in Tsc2 − / − MEFs cells. In LAM animal models, ART exerted anti-tumor effects without obvious adverse effect. Conclusions LAM patients exhibit abnormal iron metabolism independent of VEGF-D level. Ferroptosis inducer ART holds promise as a therapeutic novel approach for treating LAM. |
| format | Article |
| id | doaj-art-d4f0149470984d838fe2d7bb57f0734d |
| institution | DOAJ |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj-art-d4f0149470984d838fe2d7bb57f0734d2025-08-20T03:16:41ZengBMCRespiratory Research1465-993X2025-05-0126111410.1186/s12931-025-03285-8Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in LymphangioleiomyomatosisWenxue Bai0Shengding Zhang1Lijuan Hua2Dongyuan Wang3Mengyao Guo4Xuezhao Wang5Ying Zhou6Yong Cao7Qi Wang8Ni Zhang9Bin Xue10Min Xie11Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Nephrology, State Key Laboratory of Reproductive Medicine, Children’s Hospital of Nanjing Medical UniversityDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Sirolimus, the therapy choice for lymphangioleiomyomatosis (LAM), displayed cytostatic but not cytocidal action, with disease recurrence after withdrawal. The aim of this study is to identify novel potential biomarkers and therapeutic strategies for LAM patients. Methods TMT-labeling proteomics was utilized for screening the differentially expressed proteins (DEPs) in the plasma of 10 LAM patients and 6 controls. Plasma levels of transferrin (TRF), ferritin (FRT) and beta2-microglobulin (B2M) were validated in a cohort of 30 LAM patients and 20 controls. The diagnostic efficacy of TRF with/without VEGF-D was assessed using ROC curve analysis. The therapeutic effects of a ferroptosis inducer artesunate (ART) were evaluated both in vitro Tsc2 − / − MEFs cells and in xenograft LAM models. Results Proteomics analysis revealed 132 DEPs between LAM patients and controls, which primarily enriched in the regulation of iron ion transport. LAM patients had decreased TRF, elevated FRT and B2M levels compared with controls in the confirmation cohort (p = 0.0386, p = 0.0327 and p = 0.0155, respectively) which independent with VEGF-D level or rapamycin therapy. TRF positively correlated with both FEV1% predicted (r = 0.4486, p = 0.0251) and DLCO% predicted (r = 0.4018, p = 0.0516) of LAM patients. The combination of TRF and VEGF-D showed superior diagnostic value compared to individual indicator. ART induced the ferroptosis and inhibited the growth in Tsc2 − / − MEFs cells. In LAM animal models, ART exerted anti-tumor effects without obvious adverse effect. Conclusions LAM patients exhibit abnormal iron metabolism independent of VEGF-D level. Ferroptosis inducer ART holds promise as a therapeutic novel approach for treating LAM.https://doi.org/10.1186/s12931-025-03285-8LAMIron metabolismTRFFerroptosisART |
| spellingShingle | Wenxue Bai Shengding Zhang Lijuan Hua Dongyuan Wang Mengyao Guo Xuezhao Wang Ying Zhou Yong Cao Qi Wang Ni Zhang Bin Xue Min Xie Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis Respiratory Research LAM Iron metabolism TRF Ferroptosis ART |
| title | Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis |
| title_full | Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis |
| title_fullStr | Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis |
| title_full_unstemmed | Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis |
| title_short | Iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in Lymphangioleiomyomatosis |
| title_sort | iron metabolism disorder and artesunate inhibiting tumor growth by inducing ferroptosis in lymphangioleiomyomatosis |
| topic | LAM Iron metabolism TRF Ferroptosis ART |
| url | https://doi.org/10.1186/s12931-025-03285-8 |
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