Du Xinqian, Zhang Xinyu, Wang Zhe, Wang Dan, Li Yunqi, Liu Zengqing, Miao Qing, Zhang Hanxiao, Duan Luo, Hu Yue, Zhang Muzhi, Liu Jie, Lv Zhe, Chen Yan, Wang Wei, Sun Ying, Cui Ye
Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Department of Clinical Laboratory, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
Am J Physiol Cell Physiol. 2025 Aug 6. doi: 10.1152/ajpcell.00140.2025.
Pulmonary fibrosis, a life-threatening respiratory condition affecting millions globally, is characterized by progressive lung scarring that severely compromises respiratory function. With few effective treatment options available, it carries a poor prognosis for those affected. Disrupted iron homeostasis is increasingly implicated in its pathogenesis, yet the precise mechanisms linking iron overload to fibrotic progression remain elusive. This study unveils a novel pathway by which iron accumulation orchestrates fibrotic remodeling via secreted phosphoprotein 1 (SPP1)-mediated reprogramming of alveolar type 2 (AT2) cells. Using an integrated approach combining analysis of public single-cell and single-nucleus RNA sequencing datasets with functional validation across multiple murine models of pulmonary fibrosis (iron-induced, bleomycin-induced, and silica-induced), we demonstrate that iron overload within AT2 cells triggers a coordinated transcriptional cascade affecting iron handling, immune cell recruitment, and cellular differentiation. Mechanistically, SPP1 emerges as a key mediator, functioning both externally as a paracrine signal for macrophage recruitment following iron-induced secretion from AT2 cells, and internally as a driver of pathological epithelial transitions, specifically fostering the development of a alveolar intermediate phenotype. The clinical relevance of these findings is substantiated by analysis of human idiopathic pulmonary fibrosis specimens using publicly available single-cell and spatial transcriptomic datasets. These analyses reveal conserved pathway activation and a distinctive spatial organization of SPP1-expressing AT2 cells within remodeled tissue microenvironments, notably in close proximity to macrophages. By establishing SPP1 as a critical nexus between iron dysregulation and fibrotic progression, our work identifies the SPP1 signaling axis as a compelling therapeutic target for this devastating condition.
肺纤维化是一种危及生命的呼吸系统疾病，全球数百万人受其影响，其特征是进行性肺瘢痕形成，严重损害呼吸功能。由于有效的治疗选择很少，因此对患者来说预后很差。铁稳态失调越来越多地与其发病机制有关，但将铁过载与纤维化进展联系起来的精确机制仍不清楚。本研究揭示了一种新的途径，即铁积累通过分泌磷蛋白1（SPP1）介导的2型肺泡（AT2）细胞重编程来协调纤维化重塑。通过将公共单细胞和单核RNA测序数据集的分析与多种肺纤维化小鼠模型（铁诱导、博来霉素诱导和二氧化硅诱导）的功能验证相结合的综合方法，我们证明AT2细胞内的铁过载触发了一个协调的转录级联反应，影响铁处理、免疫细胞募集和细胞分化。从机制上讲，SPP1是一个关键介质，在外部作为AT2细胞铁诱导分泌后巨噬细胞募集的旁分泌信号，在内部作为病理性上皮转变的驱动因素，特别是促进肺泡中间表型的发展。使用公开可用的单细胞和空间转录组数据集对人类特发性肺纤维化标本进行分析，证实了这些发现的临床相关性。这些分析揭示了重塑组织微环境中保守的信号通路激活以及表达SPP1的AT2细胞的独特空间组织，特别是在巨噬细胞附近。通过将SPP1确立为铁失调与纤维化进展之间的关键联系，我们的工作确定了SPP1信号轴是这种毁灭性疾病极具吸引力的治疗靶点。
