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Background <p>Pulmonary fibrosis occurs when myofibroblasts and the extracellular matrix (ECM) excessively accumulate in the lung interstitium. Detailed studies elucidating the role of cleavage and polyadenylation-specific factor 6 (CPSF6) during fibroblast-myofibroblast transition (FMT) remain limited.</p> Methods <p>A silica-induced mouse pulmonary fibrosis model and a transforming growth factor-β1 (TGF-β1) induced fibroblast activation model were performed to investigate the role and mechanism of CPSF6. The expression of CPSF6 and profibrotic markers was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, Western blotting, and immunofluorescence assays. Dual-luciferase reporter gene assays and RNA immunoprecipitation (RIP) assays were performed to investigate the association between RUNX1 3' untraslated region (3′UTR) and miR-30a-5p.</p> Results <p>CPSF6 was downregulated in silica-induced murine fibrotic lung tissues and primary fibroblasts. Silencing CPSF6 via adeno-associated virus (AAV) in vivo exacerbated pulmonary fibrosis, while ectopic CPSF6 expression mitigated the condition. TGF-β1 effectively decreased CPSF6 expression in fibroblasts (MRC-5 and mouse primary lung fibroblast). CPSF6 overexpression blocked the profibrotic effect of TGF-β1, while inhibition of CPSF6 was found to trigger FMT. Notably, Runt-related transcription factor 1 (RUNX1), a crucial transcription factor implicated in fibrosis, was identified as a downstream effector of CPSF6. Mechanistically, CPSF6 loss favored the utilization of the proximal poly (A) site in the 3'UTR of RUNX1, leading to the production of a short 3'UTR RUNX1 transcript and more protein by avoiding being targeted for degradation by miR-30a-5p.</p> Conclusions <p>CPSF6 is implicated in the pathogenesis of fibrosis through its function in fibroblast activation, thereby enhancing the mechanistic understanding of fibrotic progression.</p>

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CPSF6-mediated alternative polyadenylation of RUNX1 to regulate silica-induced pulmonary fibrosis progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Huanyu Yang,
  • Li Zhang,
  • Mengjia Han,
  • Qiongxiao Wu,
  • Chengye Zhang,
  • Qi Xu

摘要

Background

Pulmonary fibrosis occurs when myofibroblasts and the extracellular matrix (ECM) excessively accumulate in the lung interstitium. Detailed studies elucidating the role of cleavage and polyadenylation-specific factor 6 (CPSF6) during fibroblast-myofibroblast transition (FMT) remain limited.

Methods

A silica-induced mouse pulmonary fibrosis model and a transforming growth factor-β1 (TGF-β1) induced fibroblast activation model were performed to investigate the role and mechanism of CPSF6. The expression of CPSF6 and profibrotic markers was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, Western blotting, and immunofluorescence assays. Dual-luciferase reporter gene assays and RNA immunoprecipitation (RIP) assays were performed to investigate the association between RUNX1 3' untraslated region (3′UTR) and miR-30a-5p.

Results

CPSF6 was downregulated in silica-induced murine fibrotic lung tissues and primary fibroblasts. Silencing CPSF6 via adeno-associated virus (AAV) in vivo exacerbated pulmonary fibrosis, while ectopic CPSF6 expression mitigated the condition. TGF-β1 effectively decreased CPSF6 expression in fibroblasts (MRC-5 and mouse primary lung fibroblast). CPSF6 overexpression blocked the profibrotic effect of TGF-β1, while inhibition of CPSF6 was found to trigger FMT. Notably, Runt-related transcription factor 1 (RUNX1), a crucial transcription factor implicated in fibrosis, was identified as a downstream effector of CPSF6. Mechanistically, CPSF6 loss favored the utilization of the proximal poly (A) site in the 3'UTR of RUNX1, leading to the production of a short 3'UTR RUNX1 transcript and more protein by avoiding being targeted for degradation by miR-30a-5p.

Conclusions

CPSF6 is implicated in the pathogenesis of fibrosis through its function in fibroblast activation, thereby enhancing the mechanistic understanding of fibrotic progression.