Metabolic reprogramming of the myofibroblast plays a fundamental role in the pathogenesis of fibrosing
interstitial lung diseases. Here, we characterized the in vitro and in vivo metabolic and antifibrotic effects of IM156, an oxidative phosphorylation (OXPHOS) modulator that acts by inhibiting
protein complex 1. In vitro, IM156 inhibited
transforming growth factor β (TGFβ)-dependent increases in mitochondrial oxygen consumption rate and expression of myofibroblast markers in human pulmonary fibroblasts without altering cell viability or adding to TGFβ-induced increases in the extracellular acidification rate. IM156 significantly increased cellular
AMP-activated protein kinase (AMPK) phosphorylation and was 60-fold more potent than
metformin. In vivo, chronic
oral administration of IM156 was highly distributed to major peripheral organs (i.e., lung, liver, kidney, heart) and had significant dose-related effects on the plasma metabolome consistent with OXPHOS modulation and AMPK activation. IM156 increased glycolysis, lipolysis, β-oxidation, and
amino acids and decreased
free fatty acids, tricarboxylic acid cycle activity, and
protein synthesis. In the murine
bleomycin model of
pulmonary fibrosis, daily
oral administration of IM156, administered 7 days after
lung injury, attenuated body/lung weight changes and reduced lung
fibrosis and inflammatory cell infiltration. The plasma exposures of IM156 were comparable to well tolerated doses in human studies. In conclusion, the metabolic and antifibrotic effects of IM156 suggest that OXPHOS modulation can attenuate myofibroblast metabolic reprogramming and support testing IM156 as a
therapy for
idiopathic pulmonary fibrosis and other fibrotic diseases. SIGNIFICANCE STATEMENT: Fibrosing
interstitial lung diseases have a poor prognosis, and current antifibrotic treatments have significant limitations. This study demonstrates that attenuation of fibrogenic metabolic remodeling, by modulation of oxidative phosphorylation with IM156, prevents myofibroblast phenotype/
collagen deposition and is a potentially effective and translational antifibrotic strategy.