BCL9 inhibition promotes fibroblast lipogenesis by regulating macrophage–fibroblast interactions to attenuate pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with an urgent need for novel therapeutic strategies. M2 macrophage-derived TGF-β1 promotes fibroblast myogenesis, contributing to IPF pathogenesis. Targeting macrophage polarization and fibroblast function thus represents an effective therapeutic approach for treating IPF. Here, we identify B-cell lymphoma 9 (BCL9) as a key upstream regulator implicated in IPF pathogenesis. We demonstrate that BCL9 drives the macrophage M2 program through the MerTK-ERK-SPP1 axis. Notably, pharmacological inhibition of BCL9 with our novel peptide, hsBCL9 Z96 , effectively attenuates pulmonary fibrosis by reprogramming macrophage-fibroblast crosstalk. Specifically, BCL9 inhibition promotes fibroblast lipogenesis via TGF-β1 signaling, which in turn supports alveolar type 2 (AT2) cell expansion. This macrophage–orchestrated fibroblast phenotypic switch from myogenic to lipogenic is visually corroborated by spatial transcriptomic analyses and immunofluorescence staining of human lung tissues. Functionally, the pathological role of BCL9 and efficacy of hsBCL9 Z96 are validated in human cellular models, including IPF patient-derived cells, confirming its translational significance. Collectively, our findings not only elucidate a novel BCL9-driven macrophage–fibroblast–AT2 cell axis in IPF but also establish hsBCL9 Z96 as a promising first-in-class therapeutic candidate, providing a strong rationale for targeting BCL9-mediated Wnt signaling in clinical IPF treatment.
Authors
- Bingshun Wang (ORCID: https://orcid.org/0000-0002-0435-2543)
- Xiaojin Wang (ORCID: https://orcid.org/0000-0002-1912-7939)
- Dafu Zhu (ORCID: https://orcid.org/0000-0001-8301-7999)
- Likun Gong (ORCID: https://orcid.org/0000-0002-1896-4188)
- Anqi Li (ORCID: https://orcid.org/0000-0002-3037-9483)
- Huiyu Li (ORCID: https://orcid.org/0000-0002-1977-3981)
- Ming‐Wei Wang (ORCID: https://orcid.org/0000-0001-6550-9017)
- Di Zhu (ORCID: https://orcid.org/0000-0002-5412-9323)
- Fenglian He
- Mei Feng (ORCID: https://orcid.org/0000-0001-6605-1941)
- Rongchen Liu
- Yuxuan Dong (ORCID: https://orcid.org/0000-0002-8224-306X)
- Yuan Zhang
- Ling Zhang
- Zhuyi Xi
- Jing Chen
- Xiaoxuan Lu
- Li Sun
- Wenjie Wang
- Yejun Wu
- Guanglin Zhong
- Yuan Si
- Mengmeng Zhao
- Jing Chen
Institutions
- Shenyang Pharmaceutical University (CN)
- Tongji University (CN)
- Nanjing University of Chinese Medicine (CN)
- Shanghai Medical College of Fudan University (CN)
- Guilin Medical University (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Ruijin Hospital (CN)
- Fudan University Shanghai Cancer Center (CN)
- RIKEN BioResource Research Center (JP)
- Shanghai Institute of Materia Medica (CN)
- Shanghai Pulmonary Hospital (CN)
- Shandong Academy of Pharmaceutical Sciences (CN)
- The University of Tokyo (JP)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2026-08-03
- DOI
- https://doi.org/10.1038/s41392-026-02753-x
- Primary Topic
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality
- State Key Laboratory of Drug Research
- National Key Research and Development Program of China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences