Glycolysis Reprogramming in Idiopathic Pulmonary Fibrosis: Unveiling the Mystery of Lactate in the Lung

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by excessive deposition of fibrotic connective tissue in the lungs. Emerging evidence suggests that metabolic alterations, particularly glycolysis reprogramming, play a crucial role in the pathogenesis of IPF. Lactate, once considered a metabolic waste product, is now recognized as a signaling molecule involved in various cellular processes. In the context of IPF, lactate has been shown to promote fibroblast activation, myofibroblast differentiation, and extracellular matrix remodeling. Furthermore, lactate can modulate immune responses and contribute to the pro-inflammatory microenvironment observed in IPF. In addition, lactate has been implicated in the crosstalk between different cell types involved in IPF; it can influence cell-cell communication, cytokine production, and the activation of profibrotic signaling pathways. This review aims to summarize the current research progress on the role of glycolytic reprogramming and lactate in IPF and its potential implications to clarify the role of lactate in IPF and to provide a reference and direction for future research. In conclusion, elucidating the intricate interplay between lactate metabolism and fibrotic processes may lead to the development of innovative therapeutic strategies for IPF.

Keywords: IPF; glycolysis reprogramming; lactate; metabolism; pathogenesis.

Figure 1

Cellular glycolysis and lactate metabolism play important roles in cellular energy metabolism. Cells take up glucose and generate pyruvate, which is then catalyzed by lactate dehydrogenase to produce lactate. Cells can export or uptake lactate through monocarboxylate transporters (MCTs), and the lactate taken up by cells is oxidized to pyruvate, entering the TCA cycle. Additionally, the lactate receptor GPR81 on the cell membrane can receive lactate signals and inhibit intracellular lipolysis by suppressing cAMP production.

Figure 2

The role of YAP/TAZ in regulating glycolytic reprogramming in lung fibrosis. The integrin–FAK–YAP/TAZ signal axis promotes the expression of marker genes for lung fibrosis. YAP/TAZ promotes enhanced glycolysis in cells, and the enhanced glycolysis strengthens the nuclear translocation of YAP/TAZ. Additionally, the key glycolytic enzyme HK2 is necessary for the nuclear translocation of YAP/TAZ. PFK1 can bind to TEADs and promote their functional and biochemical cooperation with YAP/TAZ.

Figure 3

Lactate potentially regulates three major cell populations in the lungs, including the modulation of energy metabolism in epithelial cells, induction of fibroblast differentiation, promotion of macrophage polarization towards a pro-inflammatory phenotype, and regulation of histone acetylation. These regulatory effects contribute to the progression of IPF.

Figure 4

Diagram illustrating the impact of lactate on intracellular signal transduction. Lactate mediates pH-dependent activation of TGF-β, thereby promoting the expression of fibrosis mediators mediated by SMADs proteins. The accumulation of lactate and the progression of oxidative phosphorylation leads to the generation of ROS, thereby inducing the activation of oxidative stress signaling pathways. Lactate can increase intracellular Ca²⁺ through GPR81 mediation, activate calcineurin, further enhancing CaMK activity, and induce mitochondrial biogenesis. Additionally, the activation of GPR81 inhibits intracellular cAMP levels, leading to decreased PKA activity.

Figure 5

Lactate shuttling plays a role in the regulation of physiological and pathological processes in the lungs. In conditions of lung injury, elevated glycolysis in the lungs leads to the production of lactate by various cell types, which enters the alveolar environment. This lactate induces polarization of macrophages, resulting in the production of pro-fibrotic factors, recruitment of interstitial cells, and activation of fibroblasts. Lactate stimulation also leads to abnormal proliferation or apoptosis of epithelial cells, causing disruption of pulmonary epithelial integrity. Furthermore, the elevated levels of lactate in the lungs result in insufficient breakdown of lipids within the alveoli, leading to the accumulation of a large amount of lipids in the alveolar space. Lactate from the systemic circulation enters the pulmonary vasculature and contributes to a decrease in pH in the lung environment, promoting lung fibrosis development.