Targeting PIM1 by Bruceine D attenuates skin fibrosis via myofibroblast ferroptosis
Skin pan-fibrosis diseases—such as hypertrophic scar (HS), keloid scar (KS), and systemic sclerosis (SSc)—pose significant threats to patients' health and quality of life. In this study, the authors conducted both in vivo and in vitro experiments and discovered that the serine/threonine kinase...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-05-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725001326 |
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| Summary: | Skin pan-fibrosis diseases—such as hypertrophic scar (HS), keloid scar (KS), and systemic sclerosis (SSc)—pose significant threats to patients' health and quality of life. In this study, the authors conducted both in vivo and in vitro experiments and discovered that the serine/threonine kinase PIM1 is upregulated in the myofibroblasts of human HS, KS, and SSc tissues, as well as in various animal models of skin fibrosis. Overexpression of PIM1 enhanced the profibrotic phenotypes of human hypertrophic scar fibroblasts (HSFs), which serve as key effector cells in the pathogenesis of skin pan-fibrosis diseases. Through high-throughput screening and subsequent laboratory assays, we identified the small molecule Bruceine D (BD) as a direct binder of PIM1. BD promoted ferroptosis in HSFs by selectively suppressing the PIM1-KEAP1-NRF2 pathway through augmented degradation of PIM1. In various in vivo models-including a hypertrophic scar mouse model, a rabbit ear hypertrophic scar model, and a bleomycin (BLM)-induced skin fibrosis mouse model-BD effectively attenuated fibrotic phenotypes. Collectively, these findings demonstrate that PIM1 serves as a common biomarker and therapeutic target for skin pan-fibrosis diseases. BD mitigates skin fibrosis by activating ferroptosis via PIM1 inhibition, highlighting its great translational potential and high promise to be developed to a clinical drug in treating these conditions, especially those with abnormally elevated PIM1 expression. |
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| ISSN: | 2213-2317 |