Unraveling the therapeutic potential of neochlorogenic acid Cu-supramolecular complexes in acute lung injury: Targeting PI3K/NF-κB/iNOS pathway through spatial metabolomics-guided

Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory diseases with high global incidence and mortality. Current therapeutic approaches remain limited, necessitating urgent development of novel treatments. Supramolecular complexes have gained attention in biomedicine due to their unique structural and functional properties. Purpose This study aimed to evaluate the therapeutic potential of neochlorogenic acid-copper supramolecular complexes (NA-Cu) against ALI/ARDS, building on prior evidence of its anti-inflammatory effects in vitro, and to elucidate its underlying metabolic mechanisms. Study design In vivo experimental investigation using an ALI model to assess NA-Cu's effects on lung pathology, inflammatory markers, and metabolic pathways. Mechanistic insights were validated through integrated metabolomics and molecular pathway analysis. Methods The therapeutic efficacy of neochlorogenic acid-copper supramolecular complexes (NA-Cu) was assessed by quantifying its effects on lung edema severity and pro-inflammatory cytokine expression levels (IL-1β, IL-6, TNF-α) in an ALI model. Mechanistic profiling was performed using an integrated analytical approach combining air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) with untargeted metabolomics to map spatial metabolic alterations. Subsequently, we screened dysregulated metabolic pathways and signaling cascades, with emphasis on the PI3K/NF-κB/iNOS axis. Validation studies established correlations between NA-Cu-induced metabolic shifts and key therapeutic outcomes, including anti-inflammatory efficacy and histological protection of lung tissue. Results This study further found that neochlorogenic acid-copper supramolecular complexes can improve edema in lung tissue by inhibiting the expression of IL-1β, IL-6, and TNF-α. The anti-ALI metabolism mechanism of NA-Cu is revealed through AFADESI-MSI combined with metabolomics. It was found that supramolecular complexes mainly affects sphingolipid metabolism, linoleic acid metabolism, α linolenic acid metabolism, ether lipid metabolism, glycerol phospholipid metabolism, arachidonic acid metabolism and PI3K/NF-κB/iNOS pathway to improve protection of lung tissue. Conclusion NA-Cu demonstrates robust anti-ALI/ARDS efficacy by synergistically suppressing inflammation and reprogramming lipid metabolism. This study validates the therapeutic promise of supramolecular complexes for ALI treatment and provides novel mechanistic insights into their mode of action.