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This study, based on an OVA-sensitized mouse model, systematically elucidates the molecular mechanisms through which 20 nm polystyrene nanoplastics (PS-NPs) exacerbate asthma. A series of assessments were conducted, including measurements of airway hyperresponsiveness (AHR), histopathological analysis of lung tissue using HE, PAS and Masson staining, immunohistochemical detection of phospholipase A2 (PLA2) and TRPV1 expression, quantification of serum immunoglobulins and tissue cytokines, as well as lung metabolomics and gut microbiota profiling. Exposure to PS-NPs activated PLA2 in lung tissue, leading to the accumulation of arachidonic acid metabolites such as prostaglandin E2 and leukotriene B4. This process increased TRPV1 channel expression and promoted the release of neuropeptides including substance P and calcitonin gene-related peptide. The resulting cascade activated the NF-κB signaling pathway, thereby enhancing Th2-type inflammatory responses characterized by elevated IL-4, IL-5 and IL-13, reduced IFN-γ, and increased oxidative stress markers such as 8-OHdG. PS-NPs also significantly altered the gut microbiota, increasing the abundance of Pseudomonadota, Actinomycetota and Verrucomicrobiota. Gram-negative bacteria released substantial amounts of hexa-acylated LPS, which activated the intestinal TLR4/NF-κB pathway and promoted pulmonary inflammation through the gut-lung axis. Furthermore, dysbiosis-induced reductions in short-chain fatty acid production and abnormalities in glycerophospholipid and amino acid metabolism further enhanced pulmonary PLA2 activity, forming a PLA2-TRPV1-neuroimmune positive feedback loop that aggravated airway hyperresponsiveness and lung tissue damage. Overall, this study suggests the central role of a metabolism-immune-neuroinflammatory network mediated by the gut-lung axis in asthma aggravated by PS-NPs, providing new insights into the respiratory toxicity of environmental nanoplastics.