Epitranscriptomics, immunometabolism, and NETosis: unlocking novel mechanisms of traditional Chinese medicine in COPD
TL;DR
The bidirectional metabolism-m6A crosstalk as a theoretical framework requiring experimental validation, and single-cell m6A sequencing, spatial metabolomics, and CRISPR screening as tools to accelerate precision TCM for COPD are outlined.
Abstract
Chronic obstructive pulmonary disease (COPD) is driven by self-perpetuating inflammation that resists conventional therapies. Recent evidence reveals three interconnected pathogenic layers: immunometabolic reprogramming, m6A epitranscriptomic dysregulation, and excessive NETosis with defective resolution. Pathogenic immune cells shift toward aerobic glycolysis and impaired fatty acid oxidation, sustaining pro-inflammatory phenotypes and corticosteroid resistance. m6A modifications may control the stability of key transcripts such as MALT1, IL-17, and PADI4, as suggested by emerging evidence. A recent rat COPD model study reported that the Shenqi Tiaoshen Formula reduced METTL16-mediated m6A methylation of MALT1, though human replication is lacking. Concurrently, neutrophil extracellular traps (NETs) damage lung tissue and expose autoantigens, accompanied by failed resolution. Traditional Chinese Medicine (TCM)—including Shenqi Tiaoshen Formula, baicalin, berberine, astragaloside IV, and curcumin—can reprogram metabolism via AMPK, modulate m6A writers/erasers, inhibit NETosis, and upregulate SPMs in preclinical models. However, most evidence derives from non-COPD models or uses supraphysiological concentrations; the translational gap to human COPD remains substantial. We discuss the bidirectional metabolism-m6A crosstalk as a theoretical framework requiring experimental validation, and outline single-cell m6A sequencing, spatial metabolomics, and CRISPR screening as tools to accelerate precision TCM for COPD.