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

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.