CHAU-CHUNG WUCHIH-FAN YEHLee, Ying-TungYing-TungLeeShih, Ying-ChunYing-ChunShihChen, Yen-TingYen-TingChenHung, Chen-TingChen-TingHungYou, Ming-YiMing-YiYouWu, Pei-ChenPei-ChenWuShentu, Tzu-PinTzu-PinShentuHuang, Ru-TingRu-TingHuangLin, Yu-ShanYu-ShanLinWu, Yueh-FengYueh-FengWuSUNG-JAN LINFRANK LEIGH LUPO-NIEN TSAOLin, Tzu-HungTzu-HungLinLo, Shen-ChuanShen-ChuanLoTseng, Yi-ShuanYi-ShuanTsengWu, Wan-LinWan-LinWuCHIUNG-NIEN CHENWu, Chau-ChungChau-ChungWuSHUEI-LIONG LINSperling, Anne IAnne ISperlingGuzy, Robert DRobert DGuzyFang, YunYunFangKAI-CHIEN YANG2022-01-182022-01-182020-08-262041-1723https://scholars.lib.ntu.edu.tw/handle/123456789/592630Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.enMESENCHYMAL TRANSITION; INHIBITION; INDUCTION; PATHWAYS; FAMILY; TRIAL[SDGs]SDG3cell component; cell organelle; gene; gene expression; numerical model; protein; public health; Mus; bleomycin; PC-TRP protein, mouse; protein disulfide isomerase; thioredoxin; transforming growth factor beta1; TXNDC5 protein, human; animal; C57BL mouse; chemistry; disease model; endoplasmic reticulum stress; fibrosing alveolitis; gene deletion; genetics; human; knockout mouse; lung fibrosis; male; metabolism; mouse; pathology; protein folding; protein stability; signal transduction; upregulation; Animals; Bleomycin; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Deletion; Humans; Idiopathic Pulmonary Fibrosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Disulfide-Isomerases; Protein Folding; Protein Stability; Pulmonary Fibrosis; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Thioredoxins; Transforming Growth Factor beta1; Up-Regulationjournal article10.1038/s41467-020-18047-x328481432-s2.0-85089907835WOS:000567549300002https://scholars.lib.ntu.edu.tw/handle/123456789/546982