Strict control of iron homeostasis is critical for the maintenance of normal lung function. Iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (PF), but the characteristics of iron metabolism in the pathogenesis of PF and related targeting therapeutics are not well studied. In this study, we investigated the cellular and molecular characteristics of iron metabolism in fibrotic lungs and further explored the efficacy of clioquinol (CQ) for the treatment of PF as well as its functional mechanism. Iron aggregates accumulated in the lungs of patients with idiopathic PF, and FTL (ferritin light chain) transcripts were increased in their pulmonary fibroblasts. In the bleomycin (BLM)-induced PF (BLM-PF) mouse model, pulmonary iron accumulation is a very early and concomitant event of PF. Labile iron pool levels in both fibroblasts and macrophages from the BLM-PF model were elevated, and iron metabolism was dysregulated. CQ attenuated PF induced by BLM and FITC, and iron-saturated CQ did not alleviate BLM-PF. Furthermore, CQ inhibited the activation of fibroblasts, including proliferation, fibrotic differentiation, proinflammatory cytokine secretion, and migration. In conclusion, our study demonstrated that CQ, acting as an iron chelator, attenuates experimental PF through inactivation of fibroblasts, providing support for targeting iron metabolism as a basis for PF treatment.

严格控制铁稳态对于维持正常肺功能至关重要。铁在特发性肺纤维化 (PF) 患者的肺部积累，但铁代谢在 PF 发病机制中的特征和相关靶向治疗尚未得到很好的研究。在这项研究中，我们研究了纤维化肺中铁代谢的细胞和分子特征，并进一步探讨了氯碘羟喹（CQ）治疗 PF 的疗效及其功能机制。铁聚集体积聚在特发性 PF 和FTL患者的肺中（铁蛋白轻链）转录物在其肺成纤维细胞中增加。在博来霉素 (BLM) 诱导的 PF (BLM-PF) 小鼠模型中，肺铁积累是 PF 的一个非常早期的伴随事件。来自 BLM-PF 模型的成纤维细胞和巨噬细胞中的不稳定铁池水平升高，并且铁代谢失调。CQ 减弱了 BLM 和 FITC 诱导的 PF，而铁饱和的 CQ 没有减轻 BLM-PF。此外，CQ 抑制成纤维细胞的活化，包括增殖、纤维化分化、促炎细胞因子分泌和迁移。总之，我们的研究表明，CQ 作为铁螯合剂，通过灭活成纤维细胞来减弱实验性 PF，为靶向铁代谢作为 PF 治疗的基础提供支持。