Licochalcone A from Ma-Xing-Shi-Gan decoction to prevent Asthma through the inhibition of ferroptosis CD4+ T Cell by GART/HSP90α signaling pathway.

Abstract

BACKGROUND: Asthma is a heterogeneous disease characterized by chronic airway inflammation and airway hyperresponsiveness. It represents the most common chronic respiratory condition in children and remains a highly prevalent disorder worldwide. PURPOSE: We investigated that Licochalcone A (LA) from Ma-Xing-Shi-Gan decoction prevent Asthma and its mechanism. METHODS: In this study, we employed both female nude mice and BALB/c mice. To identify the potential therapeutic targets ofLA, we integrated multiple target prediction databases, including HERB, STITCH, SwissTargetPrediction, CTD, and TCMSP, utilizing a systematic network pharmacology approach. RESULTS: LA demonstrated protective effects against asthma in murine models; however, this efficacy was absent in nude mice, suggesting a T cell-dependent mechanism. Conversely, LA significantly attenuated both asthma symptoms and pulmonary fibrosis in BALB/c mice. Mechanistically, LA reduced oxidative stress in T cells within the asthma model and mitigated mitochondrial damage and ferroptosis in in vitro settings. Notably, the administration of a ferroptosis agonist abolished the protective effects of LA on T cells. Single-cell RNA sequencing identified Glycinamide ribonucleotide transformylase (GART) as a key candidate gene upregulated in asthmatic T cells. Further analysis revealed that LA suppresses the GART/Heat shock proteins 90 (Hsp90) signaling pathway. Overexpression of GART reversed the beneficial effects of LA. Molecular docking studies confirmed that LA directly binds to GART at residues Valine 57, Arginine 90, Glutamine 137, and Leucine 143. CONCLUSION: In conclusion, LA, a bioactive component of the Ma-Xing-Shi-Gan decoction, exerts therapeutic effects against asthma by regulating T cell ferroptosis via suppression of the GART/HSP90α signaling pathway. Collectively, these findings suggest that LA represents a promising therapeutic candidate for alleviating T cell-mediated ferroptosis in asthma and other respiratory diseases.