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bioRxiv · 10.1101/2022.05.23.493168

Targeting Pulmonary Fibrosis by SLC1A5 dependent Glutamine Transport Blockade

Choudhury, M.·Schaefbauer, K. J.·Kottom, T. J.·Yi, E. S.·Tschumperlin, D. J.·Limper, A. H.
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Abstract

The neutral amino acid glutamine plays a central role in TGF-{beta}-induced myofibroblast activation and differentiation. Cells take up glutamine mainly through a transporter expressed on the cell surface known as solute carrier SLC1A5. In this current work, we demonstrated that profibrotic actions of TGF-{beta} are mediated, at least in part, through a metabolic maladaptation of SLC1A5 and targeting SLC1A5 abrogates multiple facets of fibroblast activation. This approach could thus represent a novel therapeutic strategy to treat fibroproliferative diseases. We found that SLC1A5 was highly expressed in fibrotic lung fibroblasts and fibroblasts isolated from IPF lungs. The expression of profibrotic targets, cell migration, and anchorage independent growth by TGF-{beta} required the activity of SLC1A5. Loss or inhibition of SLC1A5 function enhanced fibroblast susceptibility to autophagy, suppressed mTOR, HIF, Myc signaling, and impaired mitochondrial function, ATP production and glycolysis. Pharmacological inhibition of SLC1A5 by small molecule inhibitor V-9302 shifted fibroblast transcriptional profiles from profibrotic to fibrosis resolving, and attenuated fibrosis in a bleomycin treated mouse model of lung fibrosis. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in fibrosis, laying a framework for new paradigm-shifting therapies targeting cellular metabolism for this devastating disease.

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Choudhury, M., Schaefbauer, K. J., Kottom, T. J., Yi, E. S., Tschumperlin, D. J., Limper, A. H.. 2022-05-24. Targeting Pulmonary Fibrosis by SLC1A5 dependent Glutamine Transport Blockade. https://doi.org/10.1101/2022.05.23.493168

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