Zhang ZY, Ju CY, Wu LZ, Yan H, Hong WB, Chen HZ, Yang PB, Wang BR, Gou T, Chen XY, Jiang ZH, Wang WJ, Lin T, Li FN, Wu Q

Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary ...

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fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor ? receptor I (T?RI), to disrupt the interaction of T?RI-FK506 Binding Protein12 (FKBP12), which led to activation of T?RI to phosphorylate Smad3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to Smad3 to disrupt T?RI-induced Smad3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting Smad3.

Date: Mar. 16, 2023

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