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FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice

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Abstract

Pulmonary fibrosis (PF) occurs in various end stages of lung disease, and it is characterized by persistent scarring of the lung parenchyma with excessive deposition of extracellular matrix (ECM), leading to degressive quality of life and earlier mortality. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide as a specific FOXO4 blocker, selectively induced dissociation of the FOXO4-p53 complex and nuclear exclusion of p53. Simultaneously, the p53 signaling pathway has been reported to activate in fibroblasts isolated from IPF fibrotic lung tissues and the p53 mutants cooperate with other factors that have the ability to disturb the synthesis of ECM. Yet, whether FOXO4-DRI influences the nuclear exclusion of p53 and then obstructs PF progress is still unknown. In this research, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model and activated fibroblasts model. The animal group of FOXO4-DRI therapeutic administration shows a milder pathologic change and less collagen deposition compared with the BLM-induced group. We also found the FOXO4-DRI resets the distribution of intranuclear p53 and concurrently decreased the total ECM proteins content. After further validation, FOXO4-DRI may well be a promising therapeutic approach to treating pulmonary fibrosis.

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Data availability

All the data presented in this study are available on request from the corresponding author.

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Funding

This work was supported by funds from the National Natural Science Foundation of China (Grant No. 81870057 and 82070062), the Natural Science Foundation of Hubei Province (Grant No. 2020CFA018), the Translational Medicine and Interdisciplinary Research Joint Found of Zhongnan Hospital of Wuhan University (Grant. No. ZNJC202218), and the Climbing Project for Medical Talent of Zhongnan Hospital, Wuhan University (Grant No. PDJH202205).

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Author notes

  1. Ying Liu and Qinhui Hou contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

    Ying Liu, Qinhui Hou, Rui Wang, Yuan Liu & Zhenshun Cheng

  2. Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China

    Zhenshun Cheng

  3. Hubei Engineering Center for Infectious Disease Prevention, Control and Treatment, Wuhan, China

    Zhenshun Cheng

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  1. Ying Liu
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Contributions

YiL conceived and designed research, performed experiments, analyzed data, and drafted the manuscript. QH performed experiments, analyzed data, and drafted the manuscript. RW performed animal experiments. YuL conceived and designed research and edited and revised the manuscript. ZC conceived and designed research, analyzed data, drafted the manuscript, and edited and revised the manuscript. YiL, QH, RW, YuL, and ZC approved the final version of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Ying Liu or Zhenshun Cheng.

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The animal study was reviewed and approved by the Animal Care and Use Committee of Zhongnan Hospital at Wuhan University (Approval NO. ZN2021250).

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Liu, Y., Hou, Q., Wang, R. et al. FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice. Naunyn-Schmiedeberg's Arch Pharmacol 396, 2393–2403 (2023). https://doi.org/10.1007/s00210-023-02452-2

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