Targeting NFS1-mediated ferroptosis mitigates alveolar injury in experimental idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), a lethal form of interstitial lung disorder, has recently been recognized as a ferroptosis-associated disorder, with the inhibition of ferroptosis offering promising therapeutic potential. Cysteine desulfurase (NFS1) is a pivotal ferroptosis-related gene involved in regulating ferroptotic processes in multiple diseases. Nonetheless, the involvement of NFS1-mediated ferroptosis in the pathogenesis of IPF is still not well understood. The objective of this research was to explore the role of NFS1 in the advancement of IPF and to elucidate the mechanisms that contribute to this process. Significantly reduced levels of NFS1 were identified in the lungs of bleomycin (BLM)-challenged mice and BLM-exposed alveolar epithelial cells. The upregulation of NFS1 in alveolar epithelial cells markedly mitigated BLM-induced cell injury and ferroptosis, whereas NFS1 silencing exacerbated these effects. Moreover, BLM stimulation induced an iron-starvation response, as indicated by increased levels of IRP1 and TFR1 and decreased expression of FTH1. Notably, NFS1 overexpression reversed these changes by reducing IRP1 and TFR1 expression while upregulating FTH1 levels in BLM-stimulated alveolar epithelial cells. Furthermore, the exacerbation of ferroptosis caused by NFS1 silencing was abolished by IRP1 knockdown. In a BLM-induced IPF mouse model, NFS1 overexpression effectively alleviated lung injury and fibrosis, accompanied by suppression of the iron-starvation response and ferroptosis. Collectively, these findings demonstrate that NFS1 exerts a protective role against IPF by suppressing ferroptosis of alveolar epithelial cells through the modulation of iron-starvation response-induced iron overload. This research clarifies a previously unrecognized mechanism that governs the regulation of ferroptosis in IPF and emphasizes the potential of NFS1 as a promising therapeutic target for addressing this severe condition.