AUTHOR=Guo Xiaoshu , Xu Kai , Wang Lan , Ding Linke , Li Wenwen , Zhang Xinsheng , Zhao Weiming , Wang Ningdan , Wang Gaiping , Zhao Wenyu , Rosas Ivan , Yu Guoying 

TITLE=Triiodothyronine acts on DAO to regulate pulmonary fibrosis progression by facilitating cell senescence through the p53/p21 signaling pathway

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1433186

DOI=10.3389/fphar.2024.1433186

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>Idiopathic pulmonary fibrosis (IPF) is the result of multiple cycles of epithelial cell injury and fibroblast activation; currently, there is no clear etiology. Increasing evidence suggests that protein metabolism and amino acids play a crucial role in IPF, but the role of D-amino acids is not yet clear. The aim of this study was to identify novel mediators in order to test the hypothesis that D-amino acid oxidase (DAO) plays a significant role in the pathogenesis of IPF.</p></sec><sec><title>Methods</title><p>We analyzed DAO gene expression in patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis. We performed <italic>in vitro</italic> and <italic>in vivo</italic> assays to determine the effect of DAO on primary type II alveolar epithelial cells from mice and A549 cells.</p></sec><sec><title>Results</title><p>DAO expression was downregulated in the lungs of IPF patients and BLM-induced fibrotic mice. Treatment with D-serine (D-Ser) or drug inhibition of DAO promoted cell senescence through the p53/p21 pathway. <italic>Dao</italic><sup>−/−</sup> mice showed an intensified fibrotic response, and the anti-fibrotic role of T<sub>3</sub> was abolished.</p></sec><sec><title>Conclusion</title><p>We concluded that the DAO-p53/p21 axis might be a key anti-fibrotic pathway regulating the progress of fibrosis and facilitating the therapeutic role of T<sub>3</sub>.</p></sec>