抑制BCL9基因可通过调节巨噬细胞与成纤维细胞之间的相互作用，促进成纤维细胞的脂质生成，从而减轻肺纤维化病症。

Abstract

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.