GC1 treatment of bleomycin-induced lung fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease, characterized by hyperplasia and blocked differentiation of alveolar type2 cells (AT2s). Here, we found that sobetirome (GC1), a thyroid hormone receptor b (TRb) 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 GC1 is primarily through modulating the maladaptive activation state AT2s (MAS-AT2s) cell fate, promoting differentiation and inhibiting proliferation. Luciferase and ChiP assays reveal that TRb with GC1 directly regulate KLF2 and CEBPA, and further drive the AT1 genes expression.