Millettia speciosa reprograms the lung proteome and suppresses CCL24-driven eosinophilic inflammation in allergic asthma

<h4>Background</h4>Asthma is a Th2-skewed inflammatory disorder characterized by eosinophilic infiltration, cytokine dysregulation, and airway remodeling. Emerging evidence highlights the role of immunometabolic pathways and the gut-lung axis in asthma pathogenesis.<h4>Methods</h4>We investigate the therapeutic effects of Niudali (Millettia speciosa)<b>,</b> a traditional Chinese medicinal herb, in an ovalbumin-induced mouse model of allergic asthma using high-resolution data-independent acquisition (DIA) lung proteomics integrated with cytokine profiling.<h4>Results</h4>Niudali treatment significantly alleviated airway inflammation and eosinophilic infiltration. Proteomic analysis revealed 179 differentially expressed proteins (DEPs), with a notable finding that CCL24, a key eosinophil-recruiting chemokine, was completely suppressed in Niudali-treated mice but highly expressed in the asthma model. This highlights the central role of CCL24 inhibition in the mechanism through which Niudali mitigates eosinophil-mediated inflammation.Functional enrichment analyses revealed that Niudali modulates pathways involved in complement and coagulation cascades, lipid transport, antioxidant defense, and PPAR signaling, reflecting a shift toward immune resolution and metabolic homeostasis. Network analysis identified key hub proteins, including Alb, Apoe, Apoa1, Proc, and Serpina7, which orchestrate lipid metabolism, antioxidant functions, and immune regulation. The modulation of serpins, apolipoproteins, and extracellular space-related proteins suggests a broad immunometabolic reprogramming effect. Notably, this molecular signature aligns with the gut-lung axis paradigm, potentially reflecting microbiota-mediated modulation via short-chain fatty acids (SCFAs). Consistent with proteomic findings, bronchoalveolar lavage fluid (BALF) analyses showed significant reductions in IgE, IL-4, IL-5, and IL-6<b>,</b> further confirming suppression of Th2-mediated inflammation.<h4>Conclusion</h4>study provides proteomic evidence that Niudali treats asthma by disrupting the CCL24-eosinophil axis and rebalancing immunometabolic networks. These findings support Niudali as a promising candidate for gut-lung axis-targeted interventions in asthma and provide a systems-level framework for future microbiome metabolome integrated studies. While our findings suggest a potential link between these molecular changes and the gut-lung axis, this mechanism was not directly investigated in the present study and should therefore be considered hypothetical. Future studies incorporating microbiome and metabolomic analyses will be essential to clarify the role of gut-derived metabolites, including SCFAs, in mediating these effects.