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

  • Nat Commun. 2026 Feb 12;17(1):1214. doi: 10.1038/s41467-026-68909-z.
Yusuke Tsutsui  1 ,  Atsushi Masui  1 ,  Satoshi Konishi  1 ,  Taro Tsujimura  2 ,  Mio Iwasaki  1 ,  Takuya Yamamoto  1  2  3 ,  Shimpei Gotoh  4
Affiliations
  • 1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
  • 2. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
  • 3. Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan.
  • 4. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. [email protected].
PMID: 41680175 DOI: 10.1038/s41467-026-68909-z
Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring of lung tissue with an urgent need for effective treatments. Studies have shown that the alveolar transitional cell state (ATCS) emerges in fibrotic regions of the IPF lung. However, whether ATCS is the cause or consequence of fibrosis is controversial, and no therapeutic agents targeting the alveolar epithelial differentiation are used to treat IPF. In this study, we performed a drug screening with an in vitro pulmonary fibrosis model using fibroblast-dependent alveolar organoids derived from human induced pluripotent stem cells (iPSCs) and identified p300/CBP inhibitors as candidate therapeutic agents. Multi-omics technology revealed that ATCS induced from human iPSCs-derived alveolar organoids had a compatible profile with that reported in IPF and p300/CBP inhibitors suppressed the emergence of ATCS. Overall, these results elucidate the biological mechanisms of pulmonary fibrosis and provide a potential therapeutic target.

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