Metabolism-driven emerging acylation modifications in COPD: from elucidation of fundamental mechanisms to clinical diagnosis and treatment.

Abstract

The progression of chronic obstructive pulmonary disease (COPD) is closely associated with metabolic reprogramming in pulmonary and immune cells. Under stresses such as cigarette smoke exposure, hypoxia, and infection, cells exhibit enhanced glycolysis, impaired mitochondrial oxidative metabolism, and altered tricarboxylic acid (TCA) cycle flux, resulting in abnormal accumulation of metabolites including lactate, succinate, and various acyl-coenzyme A species. These molecules, acting as acyl donors, drive emerging lysine acylation modifications (e.g., lactylation, succinylation, crotonylation), which play pivotal regulatory roles in airway inflammation, oxidative stress, and tissue remodeling by modulating chromatin states of histones or enzymatic activities of non-histone proteins. Studies have shown that histone lactylation (e.g., H3K14la, H4K12la) markedly induces senescence in pulmonary epithelial cells by activating p53 or CD38 expression and exacerbates pathological alterations, whereas succinylation and crotonylation show potential in regulating mitochondrial homeostasis and immune transcriptional programs. Non-histone acylation also plays an important role in feedback regulation of metabolic enzyme function and in proteostasis regulation. To achieve precision diagnosis and treatment, this review established an evidence-grading system based on strength of supporting evidence, indicating that high-strength sites such as lactylation should be prioritized for clinical translation. Future precision prevention and treatment of COPD should shift from mere description of modification abundance to causal validation of key sites, and should prioritize the development of smallmolecule drugs with isoform selectivity, in combination with pulmonary local delivery technologies to balance efficacy and safety. In addition, combined evaluation of specific metabolite levels and the acylation status of key proteins is expected to enable the development of biomarkers with greater predictive capacity, providing scientific support for molecular subtyping and precision intervention in COPD.