Let-7 restrains an epigenetic circuit in AT2 cells to prevent fibrogenic intermediates in pulmonary fibrosis

Matthew J. Seasock, Md Shafiquzzaman, Maria E. Ruiz-Echartea, Rupa S. Kanchi, Brandon T. Tran, Lukas M. Simon, Matthew D. Meyer, Phillip A. Erice, Shivani L. Lotlikar, Stephanie C. Wenlock, Scott A. Ochsner, Anton Enright, Alex F. Carisey, Freddy Romero, Ivan O. Rosas, Katherine Y. King, Neil J. McKenna, Cristian Coarfa and Antony Rodriguez ()
Additional contact information
Matthew J. Seasock: Baylor College of Medicine
Md Shafiquzzaman: Baylor College of Medicine
Maria E. Ruiz-Echartea: Baylor College of Medicine
Rupa S. Kanchi: Baylor College of Medicine
Brandon T. Tran: Baylor College of Medicine
Lukas M. Simon: Baylor College of Medicine
Matthew D. Meyer: Rice University
Phillip A. Erice: Baylor College of Medicine
Shivani L. Lotlikar: Baylor College of Medicine
Stephanie C. Wenlock: University of Cambridge
Scott A. Ochsner: Baylor College of Medicine
Anton Enright: University of Cambridge
Alex F. Carisey: Texas Children’s Hospital
Freddy Romero: Baylor College of Medicine
Ivan O. Rosas: Baylor College of Medicine
Katherine Y. King: Baylor College of Medicine
Neil J. McKenna: Baylor College of Medicine
Cristian Coarfa: Baylor College of Medicine
Antony Rodriguez: Baylor College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract MicroRNA-mediated post-transcriptional regulation of lung alveolar type 2 (AT2) and AT1 cell differentiation remains understudied. Here, we demonstrate that the let-7 miRNA family plays a homeostatic role in AT2 quiescence by preventing the uncontrolled accumulation of AT2 transitional cells and promoting AT1 differentiation. Using mouse and organoid models, we show that genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells prevents AT1 differentiation and leads to KRT8 transitional cell accumulation in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing identified direct let-7 targets within an oncogene feed-forward regulatory network, including BACH1/EZH2/MYC, which drives an aberrant fibrotic cascade. Additional CUT&RUN-sequencing analyses revealed that let-7afd loss disrupts histone acetylation and methylation, driving epigenetic reprogramming and altered gene transcription in profibrotic AT2 cells. This study identifies let-7 as a central hub linking unchecked oncogenic signaling to impaired AT2 cell plasticity and fibrogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-59641-1

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