Human iPSC-based Modeling of Pulmonary Fibrosis Reveals p300/CBP Inhibition Suppresses Alveolar Transitional Cell...

Area of Science:

• Pulmonary Medicine
• Stem Cell Biology
• Drug Discovery

Background:

• Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options.
• The alveolar transitional cell state (ATCS) is observed in fibrotic lung regions, but its role in IPF pathogenesis is unclear.
• Current treatments do not target alveolar epithelial differentiation in IPF.

Purpose of the Study:

• To investigate the role of ATCS in IPF.
• To identify potential therapeutic agents for IPF by screening drugs targeting alveolar epithelial differentiation.
• To elucidate the mechanisms underlying pulmonary fibrosis.

Main Methods:

• Developed an in vitro pulmonary fibrosis model using human induced pluripotent stem cell (iPSC)-derived alveolar organoids.
• Performed drug screening on the fibrosis model.
• Utilized multi-omics technology to analyze cellular states and molecular profiles.
• Assessed the efficacy of identified candidate agents in suppressing ATCS.

Main Results:

• Identified p300/CBP inhibitors as candidate therapeutic agents for IPF.
• Confirmed that iPSC-derived alveolar organoids exhibit an ATCS profile consistent with IPF.
• Demonstrated that p300/CBP inhibitors effectively suppress the emergence of ATCS in the fibrosis model.
• Elucidated the biological mechanisms linking ATCS to pulmonary fibrosis.

Conclusions:

• p300/CBP inhibitors show promise as a therapeutic strategy for IPF by targeting ATCS.
• The study provides a potential therapeutic target and mechanism for treating pulmonary fibrosis.
• This research advances the understanding of IPF pathogenesis and offers a novel drug discovery approach.