肌成纤维细胞分化,在肺纤维化中驱动细胞外基质合成是必不可少的,需要增加糖酵解。糖酵解细胞必须输出乳酸,乳酸转运蛋白对肌成纤维细胞分化的作用尚不清楚.在这项研究中,我们调查了MCT1和MCT4,关键的乳酸转运蛋白,影响肌成纤维细胞分化和实验性肺纤维化。我们的发现表明,抑制MCT1或MCT4可在体外减少TGFβ刺激的肺成肌纤维细胞分化,并在体内减少博来霉素诱导的肺纤维化。通过全面的代谢分析,包括生物能学,稳定同位素示踪,代谢组学,以及细胞和小鼠的质谱成像,我们证明,抑制乳酸转运增强氧化磷酸化,减少活性氧的产生,并减少葡萄糖代谢物掺入纤维化肺区域。此外,我们介绍了VB253,一种新型的MCT4抑制剂,改善年轻和老年小鼠的肺纤维化,与已建立的抗纤维化疗法相当的疗效。这些结果强调了乳酸盐转运对肌成纤维细胞分化的必要性,确定MCT1和MCT4是肺纤维化的有希望的药理靶标,并支持对目前治疗选择有限的患者进行乳酸转运抑制剂的进一步评估.
结论:乳酸转运蛋白的小分子抑制剂,包括新型MCT4抑制剂VB253,重新编程成纤维细胞代谢以防止成肌成纤维细胞分化并减少博莱霉素诱导的肺纤维化。
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.