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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Lactate-associated fibroblast–macrophage signaling in idiopathic pulmonary fibrosis: evidence boundaries and immunopharmacological opportunities

  • Yuntao Wu1
  • Xinli Song1
  • Bin Liu2
  • Yuehua Han1
  • Chen Zheng3
  • Xiaoxu Zhao1
  • Tianyu Zhu3
  • Meng Yuan1
  • Huihui Li1
  • Yue Wang1
  1. 1School of Integrated Traditional Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine
  2. 2Department of Infectious Diseases, Characteristic Medical Center of Chinese People’s Armed Police Force
  3. 3School of Medical Technology, Tianjin University of Traditional Chinese Medicine
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Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by recurrent alveolar epithelial injury, maladaptive repair, fibroblast activation, and extracellular-matrix accumulation. Lactate metabolism is increasingly implicated in communication between stromal and immune cells in fibrotic lung niches through monocarboxylate transporter (MCT)-mediated transport, hydroxycarboxylic acid receptor 1 (HCAR1/GPR81) sensing, extracellular acidification, and lysine lactylation. This narrative review evaluates the evidence for directional lactate-associated fibroblast–macrophage signaling, the limits of proposed reciprocal interactions, and their therapeutic implications. Human IPF observations, experimental pulmonary-fibrosis studies, and indirect evidence from other disease contexts are separated according to disease relevance and causal resolution. The strongest direct mechanistic evidence supports lactate released by activated myofibroblasts as a stimulus for macrophage histone lactylation and profibrotic transcription, whereas reciprocal macrophage-to-fibroblast lactate feedback remains unproven. Among the lactate-associated targets reviewed, fibroblast-associated MCT4 currently has the most developed preclinical evidence package, supported by disease-relevant observations, target perturbation, and antifibrotic activity in experimental models. However, no lactate-directed therapeutic strategy has yet demonstrated clinical efficacy in IPF. HCAR1/GPR81, lactate-production pathways, and lactylation-associated machinery remain mechanistically compelling but are at earlier stages of pharmacological validation. Overall, available evidence is more consistent with lactate functioning as a context-dependent amplifier or maintenance signal than with a demonstrated uniform initiating role in IPF. Lactate-directed interventions may therefore be considered adjunctive strategies alongside established antifibrotic therapy. Further translation will require cell- and disease-stage-specific causal validation, lesion-resolved target engagement, efficacy in established fibrosis, and a therapeutic window that preserves physiological lactate metabolism.

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Cite

BibTeXRIS
BibTeX
@article{wu2026lactateassociated,
  title = {{Lactate-associated fibroblast–macrophage signaling in idiopathic pulmonary fibrosis: evidence boundaries and immunopharmacological opportunities}},
  author = {Yuntao Wu and Xinli Song and Bin Liu and Yuehua Han and Chen Zheng and Xiaoxu Zhao and Tianyu Zhu and Meng Yuan and Huihui Li and Yue Wang},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1989965},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1989965/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Lactate-associated fibroblast–macrophage signaling in idiopathic pulmonary fibrosis: evidence boundaries and immunopharmacological opportunities
AU  - Yuntao Wu
AU  - Xinli Song
AU  - Bin Liu
AU  - Yuehua Han
AU  - Chen Zheng
AU  - Xiaoxu Zhao
AU  - Tianyu Zhu
AU  - Meng Yuan
AU  - Huihui Li
AU  - Yue Wang
PY  - 2026
DA  - 2026/10/26
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1989965
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1989965/full
AB  - Idiopathic pulmonary fibrosis (IPF) is characterized by recurrent alveolar epithelial injury, maladaptive repair, fibroblast activation, and extracellular-matrix accumulation. Lactate metabolism is increasingly implicated in communication between stromal and immune cells in fibrotic lung niches through monocarboxylate transporter (MCT)-mediated transport, hydroxycarboxylic acid receptor 1 (HCAR1/GPR81) sensing, extracellular acidification, and lysine lactylation. This narrative review evaluates the evidence for directional lactate-associated fibroblast–macrophage signaling, the limits of proposed reciprocal interactions, and their therapeutic implications. Human IPF observations, experimental pulmonary-fibrosis studies, and indirect evidence from other disease contexts are separated according to disease relevance and causal resolution. The strongest direct mechanistic evidence supports lactate released by activated myofibroblasts as a stimulus for macrophage histone lactylation and profibrotic transcription, whereas reciprocal macrophage-to-fibroblast lactate feedback remains unproven. Among the lactate-associated targets reviewed, fibroblast-associated MCT4 currently has the most developed preclinical evidence package, supported by disease-relevant observations, target perturbation, and antifibrotic activity in experimental models. However, no lactate-directed therapeutic strategy has yet demonstrated clinical efficacy in IPF. HCAR1/GPR81, lactate-production pathways, and lactylation-associated machinery remain mechanistically compelling but are at earlier stages of pharmacological validation. Overall, available evidence is more consistent with lactate functioning as a context-dependent amplifier or maintenance signal than with a demonstrated uniform initiating role in IPF. Lactate-directed interventions may therefore be considered adjunctive strategies alongside established antifibrotic therapy. Further translation will require cell- and disease-stage-specific causal validation, lesion-resolved target engagement, efficacy in established fibrosis, and a therapeutic window that preserves physiological lactate metabolism.
SN  - 1663-9812
ER  -