Lactate transport

Myofibroblast differentiation depends on sustained glycolysis, and therefore on lactate export. We are defining monocarboxylate transport as a target in pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a fatal disease characterized by excessive deposition of extracellular matrix that leads to alveolar fibrosis, impaired gas exchange, and respiratory failure. Even with modern antifibrotic therapies, median survival is three to five years. Myofibroblasts are the primary effector cells of lung fibrogenesis, and excessive TGF-β signaling drives the differentiation of lung fibroblasts into myofibroblasts. Identifying the mechanisms that mediate this transition will both clarify disease pathobiology and reveal targets for antifibrotic therapy.

Metabolic reprogramming is essential for myofibroblast differentiation. Myofibroblasts exhibit increased glycolysis, lactate production, and reactive oxygen species generation, and inhibition of glycolysis prevents differentiation and ameliorates experimental fibrosis. Sustained glycolysis depends on lactate export through the monocarboxylate transporters (MCTs). Where inhibitors of the glycolytic enzymes have been limited by poor specificity and narrow therapeutic indices, MCT inhibitors have favorable pharmacologic profiles and have advanced to clinical trials in other diseases.

We found that MCT1 and MCT4 are upregulated in IPF lung and in experimental fibrosis, and that inhibiting either transporter, genetically or pharmacologically, blocks TGF-β–stimulated myofibroblast differentiation in fibroblasts from healthy donors and from patients with IPF. In mice, we showed that MCT inhibitors attenuate bleomycin-induced fibrosis with efficacy comparable to approved antifibrotics, in aged as well as young animals. We further demonstrated that lactate transport inhibition enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes incorporation of glucose carbon into fibrotic regions of the lung.

Lung from mice given bleomycin and treated with the MCT1 inhibitor AZD3965 or the MCT4 inhibitor VB124, with corresponding Ashcroft fibrosis scores. Scale bar, 200 μm. AZD3965 P = 0.004 and VB124 P = 0.002 versus bleomycin.

Current work addresses how this metabolic shift is transduced to the profibrotic transcriptional program, and which cells must be targeted in vivo for MCT inhibition to be effective. We are using fibroblast-specific conditional knockout animals to establish which cellular compartment requires lactate transport for fibrogenesis, and whether the benefit of MCT inhibition is attributable to the fibroblast itself. We are also examining the epigenetic consequences of intracellular lactate accumulation, including histone lactylation, as a candidate mechanism coupling the metabolic state of the cell to the profibrotic gene program.

Support

National Heart, Lung, and Blood Institute, R01 HL167718.

Key paper

2026

Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis Ziehr DR, Li F, Parnell KM, et al. Science Translational Medicine.

Data and code

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