LAUSR

Iron is a metal element indispensable for nearly all living organisms, as it participates in a variety of biological processes. The homeostasis of iron is essential to human health. Iron-responsive element-binding proteins (IRP1 and IRP2) bind the iron-responsive element (IRE) of mRNAs to control mRNA stability or protein translation. Abnormal iron homeostasis can lead to a broad spectrum of human diseases. The objective of this study was to investigate the role and mechanism of iron in lung fibroblast activation. We hypothesize that iron overload enhances lung fibroblast activation via the SH3 domain containing ring finger 1 (SH3RF1)/homeodomain interacting protein kinase 2 (HIPK2) pathway. Search for iron-responsive elements (SIREs) software was employed to predict IREs in human and mouse genomes. Lung fibroblast function studies were performed by determining the expression of myofibroblast marker α-smooth actin (α-SMA) using real-time PCR, Western blotting, and immunostaining and analyzing fibroblast invasion. Iron supplementation with ferric ammonium citrate (FAC) enhanced the mRNA and protein expression of α-SMA and fibroblast invasion. SH3RF1 was found to contain a novel IRE in its 3’-UTR and was down-regulated by iron treatment. Overexpression of SH3RF1 suppressed the iron-induced lung fibroblast activation. Moreover, iron treatment enhanced the expression of HIPK2 protein in lung fibroblasts, which was reduced by SH3RF1 overexpression. Knockdown of HIPK2 protein inhibited α-SMA mRNA expression. Furthermore, treatment of the lung fibroblasts with MG132 increased HIPK2 protein level, which was suppressed by SH3RF1 overexpression. In summary, iron controls lung fibroblast activation and invasion via the SH3RF1/HIPK2 regulation system and may be involved in the pathogenesis of idiopathic pulmonary fibrosis. R01 HL157450, R01HL135152 and P20GM103648 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.