Alternative Polyadenylation Contributes to Fibroblast Senescence in Pulmonary Fibrosis

Area of Science:

• Molecular Biology
• Cellular Senescence
• Pulmonary Fibrosis Research

Background:

• Idiopathic pulmonary fibrosis (IPF) is a fatal, age-related lung disease driven by progressive fibrosis.
• Fibroblast senescence and their senescence-associated secretory phenotype (SASP) contribute to IPF.
• Mechanisms of fibroblast senescence in IPF, particularly post-transcriptional regulation, remain unclear.

Purpose of the Study:

• To investigate the role of Nudix Hydrolase 21 (NUDT21) in regulating SASP expression and fibroblast senescence.
• To explore the impact of NUDT21-mediated alternative polyadenylation (APA) on IPF pathogenesis.

Main Methods:

• Examined NUDT21 expression in aging and fibrotic lung tissues, including IPF samples.
• Utilized NUDT21 knockdown in lung fibroblasts to assess effects on STAT3 signaling and SASP factors.
• Investigated NUDT21's role in a mouse model of bleomycin-induced pulmonary fibrosis.

Main Results:

• NUDT21 was downregulated in aging and fibrotic lungs, especially in IPF fibrotic foci.
• NUDT21 knockdown induced 3' UTR shortening of STAT3 components, increased STAT3 phosphorylation, and elevated SASP expression (interleukins, collagens, MMPs).
• NUDT21 deficiency exacerbated bleomycin-induced pulmonary fibrosis in mice.

Conclusions:

• NUDT21 plays a crucial role in regulating SASP expression via APA.
• NUDT21 downregulation contributes to fibroblast senescence and potentially IPF pathogenesis.
• NUDT21 is a potential therapeutic target for idiopathic pulmonary fibrosis.