# Role of lactate transporters in pulmonary fibrosis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $845,190

## Abstract

PROJECT SUMMARY / ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by excessive deposition of extracellular ma-
trix. Myofibroblasts are the primary effector cells of lung fibrogenesis. Identifying molecular mechanisms medi-
ating myofibroblast differentiation will increase our understanding of IPF pathobiology and identify new targets
for antifibrotic therapies. Metabolic reprogramming is one such molecular mechanism essential, yet the con-
nections between metabolism, myofibroblast differentiation, and pulmonary fibrosis are unknown. Our objective
is to define how a new metabolic approach, lactate transporter (MCT) inhibition, prevents myofibroblast differ-
entiation in vitro and in vivo. Our preliminary data implicate lactate transport in IPF pathobiology by showing
increased expression of lactate transporters MCT1 and MCT4 in IPF lung explants. We show that inhibition of
these transporters decreases bleomycin-induced pulmonary fibrosis and myofibroblast differentiation. Lactate
transporter inhibition promotes cellular respiration and mitochondrial efficiency. Transcription factor enrichment
analyses suggest that MCT inhibitors reverse TGFβ-stimulated expression of pro-fibrotic BRD4 target genes.
Together, these data support our central hypothesis that lactate transport inhibition reprograms fibroblast me-
tabolism to attenuate ROS production and BRD4 activation, thereby preventing myofibroblast differentiation
and pulmonary fibrosis. To test this, we will pursue three specific aims: (1) Determine the metabolic conse-
quences of lactate transport inhibition, (2) Determine how lactate transport inhibition alters myofibroblast gene
transcription, and (3) Identify the cellular therapeutic target of lactate transport inhibitors in vivo. In Aim 1, we
will test that MCT inhibition promotes cellular respiration, decreases mitochondrial membrane potential, and
decreases fibrogenic ROS production using metabolic flux analyses, molecular biosensors, and novel meta-
bolic manipulations. In Aim 2, we will test that decreased BRD4 activity is the novel molecular mechanism link-
ing MCT inhibition and myofibroblast differentiation using a gain- and loss-of-function strategy applied to MCT
and BRD4 activity coupled to ChIP-qPCR analyses of BRD4 target gene engagement and myofibroblast phe-
notypic readouts. In Aim 3, we will test that MCT expression is essential for myofibroblast differentiation and
pulmonary fibrosis in vivo using MCT1 and MCT4 conditional knockout animals combined with imaging mass
spectrometry to interrogate fibroblast metabolism in vivo and scRNAseq to quantify fibroblast differentiation.
The rationale for this work is that defining mechanistic links between metabolism, myofibroblast differentiation,
and pulmonary fibrosis will advance the prospects of metabolic therapies for the treatment of IPF. The pro-
posed research is innovative because it focuses on the essential role of lactate transporters in myofibr...

## Key facts

- **NIH application ID:** 10857188
- **Project number:** 5R01HL167718-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** William Michael Oldham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $845,190
- **Award type:** 5
- **Project period:** 2023-06-05 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857188

## Citation

> US National Institutes of Health, RePORTER application 10857188, Role of lactate transporters in pulmonary fibrosis (5R01HL167718-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10857188. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*