Mitigating Radiation Fibrosis Through Metabolic Regulation

ResultsGenomewide transcriptome profiling identified lipid oxidation and PPAR signaling, a master regulator of fatty acid oxidation (FAO), as the most significant features downregulated in RF in both humans and mice. TGF-B1, a master regulator of fibrosis, was found to mimic metabolic alterations in RF in vitro by downregulating genes in the PPAR pathway and by impairing oxidation of the fatty acid palmitate. To identify compounds that could reverse this metabolic dysregulation in RF, a pharmacogenomics analysis was performed to identify compounds that could normalize the RF transcriptome signature. Drug A was identified through this in silico approach and was shown in vitro to reverse TGF-B1-induced FAO suppression via upregulating the PPAR pathway while also decreasing TGF-B1 induced expression of pro-fibrotic proteins, collagen-1, fibronectin, and PAI-1. This effect was inhibited by the FAO inhibitor …