Epitranscriptomics, immunometabolism, and NETosis: unlocking novel mechanisms of traditional Chinese medicine in COPD

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.