Glycolytic reprogramming and cell-specific lactylation in asthma: an evidence-graded framework for testable metabolic-epigenetic profiles
TL;DR
The distinctive contribution is an evidence-graded, falsifiable framework that links metabolic state to cell- and residue-specific lactylation while making explicit what remains to be demonstrated in human asthma.
Abstract
Asthma is metabolically heterogeneous, but existing syntheses often place patient observations, animal perturbations, cross-disease mechanisms, and therapeutic concepts on the same evidentiary plane. This review addresses that problem by organizing glycolytic reprogramming and lysine lactylation through a three-tier hierarchy: human asthma observations, mechanistic perturbation in asthma-relevant models, and cross-disease or conceptual precedents. Mitochondrial and redox disturbances alter glycolytic and oxidative capacity across immune and structural cells, whereas lactate can function separately as an exported acidifying metabolite and as an intracellular substrate for site-specific lactylation. Four asthma-associated circuits have the strongest direct mechanistic support: epithelial histone H3 lysine 18 lactylation (H3K18la)–colony-stimulating factor 1 receptor (CSF1R) signaling; cluster of differentiation 4-positive (CD4+) T-cell H3K18la–dipeptidyl peptidase 4 (DPP4) regulation; mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2)-dependent polyglutamine-binding protein 1 (PQBP1) K223 lactylation coupled to protein arginine methyltransferase 5 (PRMT5) inhibition; and macrophage sirtuin 6 (SIRT6)–lactate dehydrogenase A (LDHA)–histone H4 lysine 12 lactylation (H4K12la) signaling. Their prevalence, effect size, temporal stability, and distribution across human asthma phenotypes remain unknown, so they should not be considered validated endotypes or biomarkers. We therefore propose five mechanistically anchored research profiles and sequential analytical, biological, clinical, and external-replication gates, with falsification criteria and no universal numerical cutoffs absent empirical calibration. We further distinguish airway-restricted delivery from regional and cellular selectivity and define deposition, diseased-mucus transport, cell-resolved pharmacokinetics and pharmacodynamics, intracellular target engagement, and local-to-systemic safety as translational gates. The distinctive contribution is an evidence-graded, falsifiable framework that links metabolic state to cell- and residue-specific lactylation while making explicit what remains to be demonstrated in human asthma.