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LMO7 drives profibrotic fibroblast polarization and pulmonary fibrosis in mice through TGF-β signalling

Acta Pharmacologica Sinica volume 46, pages 1930–1945 (2025)Cite this article

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive lethal disease. Profibrotic fibroblast polarization during wound healing is one of the main causes of IPF, and the molecular mechanisms involved have yet to be fully determined. LIM domain-only protein 7 (LMO7), which acts as an E3 ubiquitin ligase, is highly expressed in the lung, brain and heart and plays important roles in embryonic development, cancer progression, inflammatory bowel disease and Dreifuss muscular dystrophy (EDMD). In this study, we investigated the role of LMO7 in pulmonary fibrosis. Bleomycin (BLM)-induced lung fibrosis was established in mice. For AAV-mediated gene therapy, AAV-Lmo7 shRNA (AAV-Lmo7 shRNA) was intratracheally administered 6 days before BLM injection. Through transcriptome analysis, we found that the expression of LMO7 was significantly upregulated in the fibroblasts of IPF patients and BLM-induced mice. Knockdown of LMO7 impaired the profibrotic phenotype of fibroblasts in BLM-treated mice and in primary lung fibroblasts stimulated with TGF-β in vitro. We observed that LMO7 binds to SMAD7, mediating its degradation by polyubiquitination of lysine 70 and increasing the stability of TGF-β receptor 1 (TGFβR1). Finally, intratracheal administration of adeno-associated virus (AAV)-mediated Lmo7 shRNA significantly ameliorated the progression of BLM-induced lung fibrosis. Our results suggest that LMO7 is a promising target for blocking profibrotic fibroblast polarization for the treatment of fibrotic lung disease.

A model for the role of LMO7 in TGF-β/SMAD signaling during pulmonary fibrosis. During pulmonary fibrosis, ubiquitin E3 ligase LMO7 is up-regulated, and binds with. SMAD7. LMO7 mediates the ubiquitination of SMAD7 on Lysine 70, leading to its degradation, and further enhances the stability of transforming growth factor-beta receptor 1 (TGFβR1).

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Fig. 1: LMO7 is upregulated in the lung fibroblasts of IPF patients and in bleomycin-induced pulmonary fibrosis model mice.
Fig. 2: LMO7 deficiency attenuates bleomycin-induced pulmonary fibrosis.
Fig. 3: LMO7 deficiency in fibroblasts inhibits pulmonary fibrosis.
Fig. 4: LMO7 deficiency inhibits profibrotic fibroblast polarization in vivo.
Fig. 5: LMO7 is required for TGF-β1-induced profibrotic fibroblast polarization.
Fig. 6: LMO7 regulates TGF-β/SMAD signalling through SMAD7.
Fig. 7: LMO7 promotes the polyubiquitination of SMAD7 and the stability of TGF-β receptor 1.
Fig. 8: Adeno-associated virus (AAV)-mediated Lmo7 knockdown gene therapy attenuates bleomycin-induced pulmonary fibrosis.

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Acknowledgements

This work was supported by National Key Research and Development Program of China (2023YFA0913700), National Natural Science Foundation of China (82073858, 82173821, 82273934, 82373875, 82070561, 82072142, 82404636, 82473928, and 82370534), and the open project of Anhui Province Key Laboratory of Translational Cancer Research (No. KFKT202302).

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  1. These authors contributed equally: Lei Sun, Hai-bo Zhang, Hong-chao Jiang

Authors and Affiliations

  1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

    Lei Sun, Hai-bo Zhang, Hong-chao Jiang, Wen Li, Meng-kai Li, Xin-yi Yang, Yuan-yuan Cai, Ke-ke Xue, Yu-sen Gou, Xin-yue Liu & Feng Qian

  2. Department of Pharmacy, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, 200240, China

    Qing Liang

  3. Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China

    Lu-gen Zuo, Jian-guo Hu & Feng Qian

  4. Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China

    Lu-gen Zuo

  5. Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, China

    Jian-guo Hu

  6. Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, 233030, China

    Feng Qian

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Contributions

LS, JGH, and FQ conceived the study. HBZ, HCJ, MKL, XYY, YYC, KKX, YSG, and LGZ designed, performed, and interpreted experimental data. WL, XYL, and QL analyzed database. LS, FQ, HBZ, and HCJ wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Lei Sun, Jian-guo Hu or Feng Qian.

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Sun, L., Zhang, Hb., Jiang, Hc. et al. LMO7 drives profibrotic fibroblast polarization and pulmonary fibrosis in mice through TGF-β signalling. Acta Pharmacol Sin 46, 1930–1945 (2025). https://doi.org/10.1038/s41401-025-01488-9

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