Chlorogenic Acid Alleviates Experimental Asthma by Reprogramming DHA Metabolism to Inhibit Ferroptosis

Asthma is a chronic inflammatory disease with limited therapeutic options, highlighting the urgent need to explore alternative mechanisms and agents. Chlorogenic acid (CGA), a dietary polyphenol, exhibits anti-asthmatic properties, but its precise molecular mechanisms remain poorly understood. This study aimed to elucidate the mechanistic basis of CGA's anti-asthmatic effects, hypothesizing a central role in regulating polyunsaturated fatty acid metabolism and ferroptosis. An ovalbumin-induced murine asthma model was established in female BALB/c mice to evaluate the therapeutic efficacy of CGA through inflammatory cell counts, cytokine levels (ELISA), and lung histopathology. Integrated lung lipidomics (LC-MS/MS) was employed to profile lipid mediators and phospholipids. The underlying mechanism was investigated in erastin-induced ferroptosis in BEAS-2B cells and validated in mouse lung tissue using qPCR, immunofluorescence, and assays for reactive oxygen species (ROS) and Fe²⁺. CGA treatment significantly attenuated airway inflammation, reduced Th2 cytokine (IL-4, IL-5) and IgE levels, and ameliorated lung pathology in a dose-dependent manner. Lipidomics revealed that asthma was associated with dysregulated docosahexaenoic acid (DHA) metabolism, characterized by elevated pro-inflammatory lipid peroxidation products (e.g., 11-HDoHE, 14-HDoHE), a profile reversed by CGA intervention. Mechanistically, molecular docking and subsequent validation identified CGA as an activator of the Nrf2 antioxidant pathway, leading to upregulation of the key ferroptosis defense genes SLC7A11 and GPX4 both in vitro and in vivo. Consequently, CGA treatment suppressed erastin-induced ROS production and Fe²⁺ accumulation in BEAS-2B cells. In conclusion, this study demonstrates that CGA exerts anti-asthmatic effects by reprogramming DHA metabolism to suppress ferroptosis while enhancing antioxidant pathways. These findings reveal a novel mechanistic axis for CGA and establish that targeting lipid peroxidation-driven ferroptosis represents a promising therapeutic strategy for asthma.