MOBT Alleviates Pulmonary Fibrosis through an lncITPF–hnRNP<span style="font-variant: small-caps">-l-</span>Complex-Mediated Signaling Pathway

Abstract

Pulmonary fibrosis is characterized by the destruction of alveolar architecture and the irreversible scarring of lung parenchyma, with few therapeutic options and effective therapeutic drugs. Here, we demonstrate the anti-pulmonary fibrosis of 3-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran-7-yl(αS)-α,3,4-trihydroxybenzenepropanoate (MOBT) in mice and a cell model induced by bleomycin and transforming growth factor-β1. The anti-pulmonary fibrosis of MOBT was evaluated using a MicroCT imaging system for small animals, lung function analysis and H&E and Masson staining. The results of RNA fluorescence in situ hybridization, chromatin immunoprecipitation (ChIP)-PCR, RNA immunoprecipitation, ChIP-seq, RNA-seq, and half-life experiments demonstrated the anti-pulmonary fibrotic mechanism. Mechanistic dissection showed that MOBT inhibited lncITPF transcription by preventing p-Smad2/3 translocation from the cytoplasm to the nucleus, resulting in a reduction in the amount of the lncITPF–hnRNP L complex. The decreased lncITPF–hnRNP L complex reduced MEF2c expression by blocking its alternative splicing, which in turn inhibited the expression of MEF2c target genes, such as TAGLN2 and FMN1. Briefly, MOBT alleviated pulmonary fibrosis through the lncITPF–hnRNP-l-complex-targeted MEF2c signaling pathway. We hope that this study will provide not only a new drug candidate but also a novel therapeutic drug target, which will bring new treatment strategies for pulmonary fibrosis.

Keywords

• pulmonary fibrosis
• lncITPF
• hnRNP L
• MEF2c