Molecular Mechanisms and Therapeutic Targeting of the Macrophage Metabolic-Epigenetic Interaction Network in Chronic...

Pulmonary macrophages serve as one of the primary mediators of the complex and persistent inflammation in chronic obstructive pulmonary disease (COPD). While driven by multiple mechanisms-including oxidative stress pathways, macrophage heterogeneity, microbiome interactions, and the dynamics of acute exacerbations-the intrinsic drivers promoting continuous inflammatory amplification remain incompletely defined. Recent findings point to a bidirectional relationship between cellular metabolism and epigenetic regulation as a driver of this abnormal activation. This review outlines the biochemical components of this crosstalk, linking shifts in glucose, lipid, and glutamine metabolism to chromatin remodeling events. We detail four major molecular axes: α-ketoglutarate-dependent DNA methylation, NAD⁺/SIRT1-mediated deacetylation, the acetyl-CoA-fueled histone acetylation feedback loop, and the regulatory influence of non-coding RNAs (ncRNAs). Together, these pathways create a self-sustaining cycle where altered metabolic fluxes reshape the epigenetic landscape, which subsequently reinforces the initial metabolic abnormalities. This loop helps establish a stable "functional memory" in macrophages, accelerating alveolar damage. Finally, we discuss current gaps, including the need for spatial mapping and multi-omics integration, and evaluate how emerging targeted therapies-such as dual-inhibitors, PROTACs, and RNA-based treatments-could disrupt this pathogenic loop to provide novel preclinical strategies for COPD management.