Targeting Pulmonary Fibrosis by SLC1A5-Dependent Glutamine Transport Blockade

Abstract

The neutral amino acid glutamine plays a central role in TGF-β-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-β 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-β 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.

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis

“…S4 ). While previous studies have underscored the significance of glutamine, proline, and taurine ( 7, 58, 59 ), the role of branched chain amino acid metabolism, for instance, remains unexplored. Integrating these multi-omics data sets could unveil novel molecular targets for future drug development.…”

“…Recently, the contributions of fibroblast metabolic pathways to extracellular matrix production have garnered significant attention ( 7 ). Serine and glycine synthesis from the glycolytic intermediate 3-phosphoglycerate, and proline synthesis from glutamine, have been implicated in myofibroblast differentiation and pulmonary fibrosis ( 11, 12, 45, 58, 60 ). Intriguingly, our data indicate limited incorporation of glucose or lactate carbon into serine and minimal glutamine carbon incorporation into proline.…”

Reclaiming the Balance: Blocking Glutamine Uptake to Restrain Pulmonary Fibrosis

“…In this issue of the Journal , Choudhury and colleagues (pp. 441–455 ) present a novel glutamine-directed therapy for pulmonary fibrosis ( 9 ). Through a series of meticulously designed and executed studies, these investigators identified and validated the use of a specific neutral amino acid transporter by myofibroblasts for glutamine uptake.…”

“…Although the findings of Choudhury and colleagues ( 9 ) hold considerable significance, the potential translation of this therapy to human disease remains uncertain. For instance, previous preclinical studies have shown promise using the single bleomycin model; however, the results have been far less impressive when repeated in other clinically relevant models, such as aged mice, or the long-term bleomycin model.…”