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GPR40 activation alleviates pulmonary fibrosis by repressing M2 macrophage polarization through the PKD1/CD36/TGF-β1 pathway

Acta Pharmacologica Sinica volume 46, pages 2707–2722 (2025)Cite this article

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by complex aetiologies involving the accumulation of inflammatory cells, such as macrophages, in the alveoli. This process is driven by uncontrolled extracellular matrix (ECM) deposition and the development of fibrous connective tissues. Here, we observed that the mRNA expression of Ffar1, the gene encoding G protein-coupled receptor 40 (GPR40), is repressed, while Cd36 is increased in the bronchoalveolar lavage fluid (BALF), which is predominantly composed of alveolar macrophages, of IPF patients. Furthermore, the GPR40 protein was found to be largely adhered to macrophages and was pathologically downregulated in the lungs of bleomycin (BLM)-induced PF model mice (PF mice) compared with those of control mice. Specific knockdown of GPR40 in pulmonary macrophages by adeno-associated virus 9-F4/80-shGPR40 (AAV9-shGPR40) exacerbated the fibrotic phenotype in the PF mice, and activation of GPR40 by its determined agonist compound SC (1,3-dihydroxy-8-methoxy-9H-xanthen-9-one) effectively protected the PF mice from pathological exacerbation. Moreover, Ffar1 or Cd36 gene knockout mouse-based assays were performed to explore the mechanism underlying the regulation of GPR40 activation in pulmonary macrophages with compound SC as a probe. We found that compound SC mitigated pulmonary fibrosis progression by preventing M2 macrophage polarization from exerting profibrotic effects through the GPR40/PKD1/CD36 axis. Our results strongly support the therapeutic potential of targeting intrinsic GPR40 activation in pulmonary macrophages for IPF and highlight the potential of compound SC in treating this disease.

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Fig. 1: GPR40 is selectively enriched in pulmonary macrophages and downregulated in PF model mice and IPF patients.
Fig. 2: Macrophage-specific GPR40 deficiency exacerbates pulmonary fibrosis in mice.
Fig. 3: Compound SC alleviates PF-like pathology in mice.
Fig. 4: GPR40 activation by compound SC suppresses M2 macrophage polarization and TGF-β1 secretion in PF model mice.
Fig. 5: Activation of GPR40 decreases M2 macrophage polarization by inhibiting TGF-β1 secretion.
Fig. 6: Activation of GPR40 represses TGF-β1 secretion and M2 macrophage polarization via CD36.
Fig. 7: Activation of GPR40 reduces CD36 expression through PKD1.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82204486, 82304468), the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine (XPT82204486, XPT82304468), and the Major Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (24KJA310006).

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  1. These authors contributed equally: Hui-qi Wan, Ling-feng Xie

Authors and Affiliations

  1. Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Hui-qi Wan, Hong-lin Li, Yan Ma, Qiu-hui Li, Meng-qing Dai, Wen-jun Li, Min-yi Qian & Xu Shen

  2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China

    Ling-feng Xie & Jin-pei Zhou

  3. Pulmonary Disease Department, Nanjing Pukou District Central Hospital, Nanjing University of Chinese Medicine, Nanjing, China

    Yuan-dong Fu

  4. National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing, China

    Xu Shen

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Contributions

HQW: Investigation, Formal analysis, Validation, Methodology, Writing-original draft. LFX: Investigation, Methodology, Validation. HLL: Methodology, Validation. YM: Methodology, Validation. QHL: Investigation, Methodology. MQD: Investigation, Methodology. YDF: Resources, Formal analysis. WJL: Funding acquisition. JPZ: Conceptualization, Formal analysis. MYQ: Conceptualization, Data curation, Writing-review & editing, Funding acquisition. XS: Conceptualization, Writing-review & editing, Project administration, Funding acquisition.

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Correspondence to Jin-pei Zhou, Min-yi Qian or Xu Shen.

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Wan, Hq., Xie, Lf., Li, Hl. et al. GPR40 activation alleviates pulmonary fibrosis by repressing M2 macrophage polarization through the PKD1/CD36/TGF-β1 pathway. Acta Pharmacol Sin 46, 2707–2722 (2025). https://doi.org/10.1038/s41401-025-01558-y

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