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Serum amyloid A3 aggravates bleomycin-induced pulmonary fibrosis through Krüppel-like factor 6-dependent interlukin-36α expression

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease; however, effective clinical treatments for IPF are lacking. High serum amyloid A (SAA) expression in serum is closely related to the severity of pulmonary fibrosis, but the underlying mechanisms remain incompletely understood. This study found that the expression of endogenous SAA3 was significantly induced in mice with bleomycin-induced fibrosis. Saa3 deletion alleviated pulmonary fibrosis in mice. Additionally, recombinant IL-36α treatment aggravated fibrosis in bleomycin-induced Saa3−/− mice. Furthermore, SAA3 could induce the expression of IL-36α in macrophages through the NF-κB pathway and transcription factor Krűppel-like factor 6 (KLF6). Also, the Klf6 knockdown alleviated severe lung fibrosis after recombinant SAA3 treatment. In conclusion, our study suggested that SAA3 aggravated bleomycin-induced pulmonary fibrosis by inducing IL-36α expression in macrophages through the NF-κB–KLF6 pathway. It provides new theoretical bases and potential therapeutic targets for treating fibrosis-related diseases.

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Fig. 1: SAA3 is highly induced in BLM-induced pulmonary fibrosis.
Fig. 2: SAA3 aggravates BLM-induced pulmonary fibrosis damage.
Fig. 3: IL-36α is a main partner in the aggravating effect of SAA3 on BLM-induced pulmonary fibrosis.
Fig. 4: SAA3 induces the expression of IL-36α through NF-κB signaling pathway.
Fig. 5: SAA3 induces IL-36α expression through NF-κB-KLF6 in macrophages.
Fig. 6: SAA3 aggravates BLM-induced pulmonary fibrosis via KLF6 induction.
Fig. 7: Serum Amyloid A3 aggravates bleomycin-induced pulmonary fibrosis through Krüppel-like factor 6-dependent interlukin-36α expression.

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Data availability

The authors declare that the data supporting the findings of this study are available within the article.

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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, 82072142 and 82473928), the open project of Anhui Province Key Laboratory of Translational Cancer Research (KFKT202302), Health Profession Clinical Research Funds of the Shanghai Municipal Health Commission (Grant No. 202140315), and the Scientific Research Project funded by the Shanghai Municipal Science and Technology Commission (Grant No. 23ZR1449900). Health Profession Clinical Research Funds of the Shanghai Municipal Health Commission (Grant No. 202140315), and the Scientific Research Project funded by the Shanghai Municipal Science and Technology Commission (Grant No. 23ZR1449900).

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Authors and Affiliations

  1. Shanghai Frontiers Science Center of Drug Target Identification and Drug Delivery, Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

    Xin-yi Yang, Ying Liu, Wen Li, Hui-xing Li, Yu-wen Zhong, Feng Qian & Lei Sun

  2. Department of Clinical Medicine, First Clinical School of Medicine, Anhui Medical University, Hefei, 230031, China

    Yu-han Cao

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

    Tian-yi Liu

  4. Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200240, China

    A-jing Xu

  5. Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, and Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, Bengbu, 233030, China

    Wei Gu

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

    Qing Liang

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Contributions

LS and FQ conceived the study. LS and XYY designed, XYY, WL, YL, and QL performed, and interpreted experimental data. XYY, HXL, AJX and YWZ analyzed database. XYY, YHC, TYL and WG prepared the data visualization. LS and XYY wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Feng Qian or Lei Sun.

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Yang, Xy., Liu, Y., Li, W. et al. Serum amyloid A3 aggravates bleomycin-induced pulmonary fibrosis through Krüppel-like factor 6-dependent interlukin-36α expression. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01596-6

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