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

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.