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TRβ-agonist Sobetirome(GC-1) Attenuates Pulmonary Fibrosis via Promoting MAS-AT2s Differentiation into AT1s.

GSE246654 Mus musculus Expression profiling by high throughput sequencing 9 samples Submitted 2024/08/30 Platform GPL21103
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease, characterized by hyperplasia and blocked differentiation of alveolar type-2 cells (AT2s). Here, we found that sobetirome (GC-1), a thyroid hormone receptor β (TRβ) specific agonist, exhibits striking efficiency and safety to treat PF in two mouse models (bleomycin and silica) and one rat model. We proposed that most IPF is a type of non-thyroidal illness syndrome (NTIS) based on hormone level tests. Using lineage tracing mice and co-culture, we confirmed that the anti-fibrosis effect of GC-1 is primarily through modulating the maladaptive activation state AT2s (MAS-AT2s) cell fate, promoting differentiation and inhibiting proliferation. Luciferase and ChiP assays reveal that TRβ with GC-1 directly regulate KLF2 and CEBPA, and further drive the AT1 genes expression. AT2s-KLF2-knockout or CEBPA AAV-knockdown mice nullified the GC-1 effect of anti-fibrosis and showed an abnormal regeneration in pneumonectomy, indicating that KLF2 and CEBPA are the anti-fibrotic targets of GC-1.
Published in
TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA
Pan X, Wang L, Yang J et al. · Nature communications 2024 · PMID 39375377 · doi:10.1038/s41467-024-52827-z
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Also filed as BioProject PRJNA1033428 and SRA study SRP469104. Searching any of these in the dataset finder brings you back here.

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