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

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. 3 conditions were evaluated in mouse: Mouse + Bleomycin, sacrificed 21 days after exposure, mouse + Bleomycin + GC1, sacrificed 21 days after exposure, GC1 was given from day 11 to day 21 for mice, and control mouse + PBS, sacrificed 21 days after exposure. Each treatment had three replicates for a total of 9 RNA samples. Each replicate was composed of three mice pooled together.