CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling

Marta Bueno, Jazmin Calyeca, Timur Khaliullin, Megan Miller, Diana Álvarez, Lorena Rosas, Judith Brands, Christian M. Baker, Amro Nasser, Stephanie Shulkowski, August Mathien, Uzoukwu Nneoma O, John Sembrat, Brenton G. Mays, Kaitlin Fiedler, Scott A. Hahn, Sonia R. Salvatore, Francisco J. Schopfer, Mauricio Rojas, Peter SandnerAdam Straub, Ana L. Mora

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    Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECIIs. Deficiency of CYB5R3 in AECIIs led to sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and the sGC/cGMP/protein kinase G axis that modulates activation of the TGF-β1 signaling pathway. We demonstrate that sGC agonists (BAY 41-8543 and BAY 54-6544) are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECIIs. Taken together, these results show that CYB5R3 in AECIIs is required to maintain resilience after lung injury and fibrosis and that therapeutic manipulation of the sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.

    Original languageEnglish
    Article numbere161487
    JournalJCI insight
    Issue number5
    Early online date7 Feb 2023
    Publication statusE-pub ahead of print/First online - 7 Feb 2023


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