Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis

Fibrosis, or the accumulation of extracellular matrix, causes loss of organ function and is a common feature of many chronic diseases. To interrogate the core molecular pathways of fibrosis, we cross-examined human primary cells from various tissues treated with TGFβ. Transcriptome analyses revealed that in addition to the known TGFβ signature, top-regulated cluster of genes are involved in fatty acid metabolism. To further evaluate this observation in vivo, we characterized a renal fibrosis model through unilateral ureteral obstruction (UUO) in mice. TGFβ signaling was greatly augmented in UUO kidneys and preventive treatment with an anti-TGFβ antibody resulted in significant reduction of fibrosis. Transcriptome analysis also identified fatty acid metabolism as one of the top dysregulated pathways in UUO kidneys, which was further supported by a substantial accumulation of acylcarnitines. Additional rodent models of liver fibrosis revealed a similar metabolic signature upon fibrosis induction. Lastly, a compound library phenotypic screen for suppressers of fibrosis identified AMPK and PPAR activators. As a proof of concept, we demonstrated that pharmacological treatment of telmisartan, an angiotensin receptor and PPARγ dual-agent, significantly reduced fibrosis in UUO kidneys, suggesting that metabolic defect is integral to TGFβ signaling and fibrosis. Altogether, our work has revealed a common node of metabolic signature underlying fibrosis that could represent a promising therapeutic target for multiple fibrotic diseases.