The NRF2-LOC344887 signaling axis suppresses pulmonary fibrosis

Pengfei Liu, Gang Luo, Matthew Dodson, Cody J. Schmidlin, Yongyi Wei, Baris Kerimoglu, Aikseng Ooi, Eli Chapman, Joe GN Garcia, Donna D. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease characterized by an increase in differentiation of fibroblasts to myofibroblasts and excessive accumulation of extracellular matrix in lung tissue. Pharmacological activation of NRF2 has proved to be a valuable antifibrotic approach, however the detailed mechanisms of how NRF2 mediates antifibrotic function remain unclear. In this study, we found that the antifibrotic function of sulforaphane (SFN), an NRF2 activator, was largely dependent on LOC344887, a long noncoding RNA. Two functional AREs were identified in both the promoter and intron 1 of LOC344887, which defines LOC344887 as a novel anti-fibrotic NRF2 target gene. RNA-seq analysis revealed that LOC344887 controls genes and signaling pathways associated with fibrogenesis. Deletion or downregulation of LOC344887 enhanced expression of CDH2/N-cadherin, as well as a number of other fibrotic genes and blunted the antifibrotic effects of SFN. Furthermore, LOC344887-mediated downregulation of fibrotic genes may involve the PI3K-AKT signaling pathway, as pharmacologic inhibition of PI3K activity blocked the effects of LOC344887 knockdown. Our findings demonstrate that NRF2-mediated LOC344887 upregulation contributes to the antifibrotic potential of SFN by repressing the expression of CDH2 and other fibrotic genes, providing novel insight into how NRF2 controls the regulatory networks of IPF. This study provides a better understanding of the molecular mechanisms of NRF2 activators against pulmonary fibrosis and presents a novel therapeutic axis for prevention and intervention of fibrosis-related diseases.

Original languageEnglish (US)
Article number101766
JournalRedox Biology
Volume38
DOIs
StatePublished - Jan 2021

Keywords

  • CDH2
  • Extracellular matrix
  • LOC344887
  • NRF2
  • PI3K-AKT
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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