Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. Here we generated spatially resolved transcriptome maps of human IPF (n = 4) and bleomycin-induced mouse pulmonary fibrosis (n = 6) to address these limitations. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by transforming growth factor beta signaling alongside predicted regulators, such as TP53 and APOE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.

特发性肺纤维化（IPF）是一种进行性肺部疾病，预后不良，治疗选择有限。由于对 IPF 发病机制的了解有限以及现有临床前模型的可移植性较差，寻找有效治疗方法的努力受到阻碍。在这里，我们生成了人类 IPF (n = 4) 和博莱霉素诱导的小鼠肺纤维化 (n = 6) 的空间分辨转录组图，以解决这些局限性。我们在 IPF 肺部发现了独特的纤维化生态位，其特征是微环境中的异常肺泡上皮细胞，该微环境由转化生长因子 β 信号传导以及预测的调节因子（例如 TP53 和 APOE）主导。我们还发现，IPF 纤维化微环境中停滞的肺泡再生与急性纤维化小鼠肺中的活跃组织修复之间存在明显差异。我们的研究提供了对 IPF 转录景观的深入见解，并提出肺泡再生作为 IPF 的一种有前景的治疗策略。