Abstract：
Radiation-Induced Pulmonary Fibrosis (RIPF) frequently arises as a delayed complication following radiation therapy for thoracic cancers, encompassing lung, breast, and esophageal malignancies. Characterized by a relentless and irreversible accumulation of extracellular matrix (ECM) proteins within the lung parenchyma, RIPF presents a significant clinical challenge. While the modulation of gene expression by transcription factors is a recognized aspect in various pathologies, their specific role in the context of RIPF has been less clear. This study elucidates that ionizing radiation prompts the translocation of the transcription factor GATA3 into the nucleus. This translocation facilitates GATA3\'s binding to the NRP1 promoter, thereby enhancing the transcription and subsequent translation of NRP1. Further investigations demonstrate that the TGF-β pathway agonist, SRI-011381, can mitigate the effects of NRP1 knockdown on epithelial-mesenchymal transition (EMT) and ECM deposition, suggesting a pivotal role of the GATA3/NRP1/TGF-β axis in the pathogenesis of RIPF. In conclusion, our findings not only underscore the critical involvement of GATA3 in RIPF but also highlight the GATA3/NRP1/TGF-β signaling pathway as a promising target for therapeutic intervention in RIPF management.
摘要：
放射诱发的肺纤维化（RIPF）通常是胸癌放射治疗后的延迟并发症。包括肺，乳房,和食道恶性肿瘤.以肺实质内细胞外基质（ECM）蛋白的无情和不可逆的积累为特征，RIPF提出了重大的临床挑战。虽然转录因子对基因表达的调节是各种病理中公认的方面，它们在RIPF背景下的具体作用还不太清楚。这项研究阐明了电离辐射促使转录因子GATA3易位到细胞核中。这种易位促进GATA3与NRP1启动子的结合，从而增强NRP1的转录和随后的翻译。进一步的研究表明，TGF-β途径激动剂，SRI-011381可以减轻NRP1敲低对上皮间质转化（EMT）和ECM沉积的影响，提示GATA3/NRP1/TGF-β轴在RIPF发病机制中的关键作用。总之,我们的研究结果不仅强调了GATA3在RIPF中的关键参与,而且还强调了GATA3/NRP1/TGF-β信号通路是RIPF管理中治疗干预的有希望的靶标.
