Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo . Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.
Competing Interests: W.M.O. has received consulting fees from Nikang Therapeutics outside the scope of this research.J.R. is a consultant and shareholder for Vettore Biosciences.R.S.K. received a Discovery ILD Award from Boehringer Ingelheim and received support through the Partners Drug Development Lab from Bayer Pharmaceuticals, all outside the scope of this research.E.Y.K. received unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, and 10X Genomics. E.Y.K. has a financial interest in Novartis AG unrelated to this work.B.A.M. has received consulting fees from Actelion and Tenax and has performed investigator-initiated research with support from Deerfield, all outside the scope of this research.L.P.H. reports grants from Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and has received personal consulting fees from BIPI, Pliant Therapeutics, Clario, and Abbvie Pharmaceuticals.The remaining authors declare that they have no competing interests.