TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor alpha (TR alpha) promotes cell proliferation, while TR beta fuels cell maturation in lung regeneration. Using a specific TR beta agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TR beta in mice. Cellularly, TR beta activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TR beta activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TR beta-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis. Here, Xin Pan and colleagues found that activation of thyroid hormone receptor-beta is necessary for alveolar epithelial cell differentiation during lung repair and regeneration, and confirmed a specific agonist and molecular targets for fibrosis therapy.