This study reveals a novel mechanism by which TGF-β1 signaling regulates fibroblast phenotypic transition in pulmonary fibrosis, providing a complete path from target validation to cellular interaction analysis for IPF intervention strategies, inspiring future experimental designs to emphasize dynamic reprogramming of the immune-stromal cell axis.
Literature Overview
The article titled "BCL9 inhibition promotes fibroblast lipogenesis by regulating macrophage–fibroblast interactions to attenuate pulmonary fibrosis," published in the journal Signal Transduction and Targeted Therapy, systematically investigates the regulatory role of BCL9 in idiopathic pulmonary fibrosis (IPF). The study reveals that BCL9, a key transcriptional co-activator in the Wnt/β-catenin signaling pathway, drives M2 polarization of macrophages via the MerTK-ERK-SPP1 axis, thereby promoting the transformation of fibroblasts into myofibroblasts. In contrast, inhibition of BCL9 reverses this process, induces fibroblast lipogenesis, and supports the expansion of alveolar epithelial type II (AT2) cells, ultimately alleviating fibrosis. This work not only uncovers a novel pathological axis but also offers a more precise intervention strategy for targeting Wnt signaling.Background Knowledge
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by progressive scarring of lung tissue, ultimately leading to respiratory failure. Current treatments, such as nintedanib and pirfenidone, only slow disease progression and cannot reverse established fibrosis. Therefore, there is an urgent need to identify new molecular targets for developing therapies with greater disease-modifying potential. In recent years, increasing attention has been paid to the role of the immune microenvironment in IPF pathogenesis, particularly the M2 macrophages, which promote fibroblast activation through secretion of TGF-β1 and are considered one of the core drivers of fibrosis progression. Meanwhile, aberrant activation of the Wnt/β-catenin signaling pathway has also been widely reported to contribute to fibrosis, although broad-spectrum inhibition of Wnt often leads to severe side effects, limiting its clinical application. Thus, selectively blocking the pathogenic branch of the Wnt pathway has become a research bottleneck. This study directly addresses this challenge by focusing on BCL9, a critical but underexplored transcriptional co-activator in the Wnt pathway within IPF, proposing its potential role as a hub linking macrophage polarization and fibroblast function, thereby offering a novel entry point for targeted therapy.
Research Methods and Experiments
The research team first analyzed BCL9 expression profiles in lung tissues of IPF patients using public single-cell RNA sequencing datasets (GSE124685, GSE136831), revealing its significant upregulation in macrophages and a strong correlation with disease progression. Subsequently, by generating macrophage-specific Bcl9 knockout mice (Bcl9fl/fl Lyz2Cre) and employing a novel stabilized peptide inhibitor, hsBCL9Z96, they validated the functional role of BCL9 in a bleomycin (BLM)-induced mouse model of pulmonary fibrosis. Fibrosis severity, macrophage phenotypes, and fibroblast states were assessed using flow cytometry, histopathological staining, and qPCR. Additionally, an in vitro co-culture system (PMs and MLFs) and spatial transcriptomic analysis were used to systematically dissect the mechanisms of macrophage–fibroblast interactions. Key findings include: hsBCL9Z96 significantly reduced the proportion of M2 macrophages, suppressed TGF-β1 secretion, and decreased collagen deposition; scRNA-seq demonstrated a phenotypic shift of fibroblasts toward a lipogenic state upon BCL9 inhibition; spatial analysis confirmed the close proximity of M2 macrophages and lipofibroblasts in fibrotic regions, supporting a paracrine regulatory mechanism.Key Conclusions and Perspectives
Research Significance and Prospects
This study identifies BCL9 as a novel drug target for therapeutic development. Its specific inhibitor, hsBCL9Z96, avoids the toxicity associated with broad-spectrum Wnt inhibition, offering a wider therapeutic window. Furthermore, fibroblast phenotypic switching could serve as a potential functional biomarker for assessing treatment response in future clinical monitoring. When combined with spatial transcriptomic technologies, this may enable visualization and tracking of microenvironmental dynamics.
In terms of disease modeling, this work underscores the importance of immune-stromal interactions, suggesting that future construction of more accurate IPF models should integrate macrophage polarization states with fibroblast metabolic phenotypes—such as through conditional knockout mice or organoid co-culture systems—to better recapitulate the human disease microenvironment.
Conclusion
This study systematically uncovers the central regulatory role of BCL9 in idiopathic pulmonary fibrosis, proposing the "BCL9–macrophage–fibroblast–AT2 cell" signaling axis as a key hub in disease progression and resolution. By targeting BCL9, it is possible not only to suppress profibrotic macrophage polarization but also to actively promote the transition of fibroblasts into antifibrotic lipofibroblasts, thereby supporting alveolar regeneration. This dual mechanism surpasses the "braking" effect of traditional antifibrotic drugs, conferring true "repair" potential. From bench to bedside, this discovery lays a solid foundation for developing novel disease-modifying therapies. hsBCL9Z96, as the first peptide inhibitor targeting the BCL9/β-catenin protein interaction, demonstrates strong efficacy and specificity, and is a promising candidate for further clinical development. Future studies need to further validate its long-term safety and efficacy in more complex models, but this work undoubtedly introduces a transformative therapeutic paradigm into IPF patient care, marking a strategic shift from merely inhibiting fibrosis toward actively promoting tissue repair.
