Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT
Abstract Pulmonary fibrosis (PF) is a disease characterized by dysregulated extracellular matrix deposition and aberrant fibroblast activation. Emerging evidence implicates that dysregulated copper metabolism contributed to fibrotic pathogenesis, yet its role and the therapeutic potential of copper...
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| Language: | English |
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BMC
2025-05-01
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| Series: | European Journal of Medical Research |
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| Online Access: | https://doi.org/10.1186/s40001-025-02640-1 |
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| author | Yajun Wang Shuyang Chen Zheng Zhou Jinjun Jiang Shujing Chen |
| author_facet | Yajun Wang Shuyang Chen Zheng Zhou Jinjun Jiang Shujing Chen |
| author_sort | Yajun Wang |
| collection | DOAJ |
| description | Abstract Pulmonary fibrosis (PF) is a disease characterized by dysregulated extracellular matrix deposition and aberrant fibroblast activation. Emerging evidence implicates that dysregulated copper metabolism contributed to fibrotic pathogenesis, yet its role and the therapeutic potential of copper modulation remain underexplored. This study investigated the involvement of cuproptosis, a programmed cell death induced by intracellular copper overload, in PF and evaluated the therapeutic efficacy of the copper chelator tetrathiomolybdate (TTM). In a bleomycin (BLM)-induced murine PF model, intratracheal BLM administration elevated lung copper levels, upregulated oligomerized DLAT, and exacerbated fibrosis, as evidenced by collagen deposition, α-smooth muscle actin, and transforming growth factor-beta expression. TTM treatment significantly attenuated fibrotic progression, reduced oxidative stress, and suppressed Olig-DLAT accumulation. In vitro, copper ionophores induced cuproptosis in bronchial epithelial cells, characterized by reduced viability, elevated intracellular Cu⁺, and Olig-DLAT aggregation, which were reversed by TTM. Furthermore, TTM mitigated TGF-β-driven epithelial–mesenchymal transition (EMT) and fibroblast-to-myofibroblast transition (FMT), downregulating collagen-1 and restoring E-cadherin expression. These findings establish cuproptosis as a novel mechanistic contributor to PF and highlight TTM’s dual role in restoring copper homeostasis and inhibiting fibrogenic pathways, offering a promising therapeutic strategy for fibrotic lung diseases. |
| format | Article |
| id | doaj-art-d8635de752d249cba9835f5a0f7d3ed0 |
| institution | DOAJ |
| issn | 2047-783X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj-art-d8635de752d249cba9835f5a0f7d3ed02025-08-20T03:08:24ZengBMCEuropean Journal of Medical Research2047-783X2025-05-0130111310.1186/s40001-025-02640-1Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMTYajun Wang0Shuyang Chen1Zheng Zhou2Jinjun Jiang3Shujing Chen4Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan UniversityAbstract Pulmonary fibrosis (PF) is a disease characterized by dysregulated extracellular matrix deposition and aberrant fibroblast activation. Emerging evidence implicates that dysregulated copper metabolism contributed to fibrotic pathogenesis, yet its role and the therapeutic potential of copper modulation remain underexplored. This study investigated the involvement of cuproptosis, a programmed cell death induced by intracellular copper overload, in PF and evaluated the therapeutic efficacy of the copper chelator tetrathiomolybdate (TTM). In a bleomycin (BLM)-induced murine PF model, intratracheal BLM administration elevated lung copper levels, upregulated oligomerized DLAT, and exacerbated fibrosis, as evidenced by collagen deposition, α-smooth muscle actin, and transforming growth factor-beta expression. TTM treatment significantly attenuated fibrotic progression, reduced oxidative stress, and suppressed Olig-DLAT accumulation. In vitro, copper ionophores induced cuproptosis in bronchial epithelial cells, characterized by reduced viability, elevated intracellular Cu⁺, and Olig-DLAT aggregation, which were reversed by TTM. Furthermore, TTM mitigated TGF-β-driven epithelial–mesenchymal transition (EMT) and fibroblast-to-myofibroblast transition (FMT), downregulating collagen-1 and restoring E-cadherin expression. These findings establish cuproptosis as a novel mechanistic contributor to PF and highlight TTM’s dual role in restoring copper homeostasis and inhibiting fibrogenic pathways, offering a promising therapeutic strategy for fibrotic lung diseases.https://doi.org/10.1186/s40001-025-02640-1Pulmonary fibrosisCuproptosisTetrathiomolybdateBleomycin |
| spellingShingle | Yajun Wang Shuyang Chen Zheng Zhou Jinjun Jiang Shujing Chen Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT European Journal of Medical Research Pulmonary fibrosis Cuproptosis Tetrathiomolybdate Bleomycin |
| title | Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT |
| title_full | Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT |
| title_fullStr | Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT |
| title_full_unstemmed | Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT |
| title_short | Tetrathiomolybdate alleviates bleomycin-induced pulmonary fibrosis by reducing copper concentration and suppressing EMT |
| title_sort | tetrathiomolybdate alleviates bleomycin induced pulmonary fibrosis by reducing copper concentration and suppressing emt |
| topic | Pulmonary fibrosis Cuproptosis Tetrathiomolybdate Bleomycin |
| url | https://doi.org/10.1186/s40001-025-02640-1 |
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