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5-methoxyindole-3-carboxaldehyde attenuates alveolar type II epithelial cell senescence induced by exposure to polystyrene microplastics in pulmonary fibrosis via PI3K/AKT/mTOR signaling pathway

Ecotoxicology and Environmental Safety 2026
Yuhan Du, George Zhang, Jinzhong Zhuo, Jie Chen, D. Liu, Yiming Li, Qicai Liu, Liping Huang, Xiaoxiao Jiang, Shiyan Liang, Zhen Qin, Qingmei Wang, Qi Yu, Yuehua Chen, Shaoxi Cai, Hao Wang, Mengchen Zou, Hangming Dong

Summary

Researchers found that polystyrene microplastic exposure in mice disrupted airway microbial communities and promoted lung fibrosis through metabolic changes. The study identified a microbial metabolite called 5-methoxyindole-3-carboxaldehyde (5-MC) that was reduced by microplastic-induced dysbiosis and could attenuate lung cell aging through the PI3K/AKT/mTOR signaling pathway. The findings suggest that microplastics may drive pulmonary fibrosis by disrupting the balance of protective metabolites produced by airway microbes.

Polymers
Body Systems
Models

Microplastics, as a novel type of environmental pollutant, have garnered increasing concern for their potential threat to human health. Pulmonary fibrosis, with high mortality and limited therapy, is exacerbated by airborne contaminants like microplastics. This research assessed the pathological role of polystyrene microplastic (PS-MPs) exposure in driving airway microbial dysbiosis and subsequent fibrotic lung remodeling. Mice were intranasally instilled with PS-MPs and treated with a mixture of antibiotics. Bronchoalveolar lavage fluid was collected from the mice, and the airway microbiota, along with their associated metabolic profiles, were characterized using 16S rRNA gene sequencing, non-targeted metabolomics, and network pharmacology. Exposure to PS-MPs significantly increased the abundance of Staphylococcus, Prevotella, and Weissella in the mouse airway and altered the structure of the lung microbiota. Microbiota derived metabolites, such as 5-methoxyindole-3-carboxaldehyde (5-MC), arachidonylamide, progesterone, and oleamide, were significantly negatively correlated with Staphylococcus, Prevotella, and Weissella, with 5-MC showing the largest fold change. Experimental data demonstrated that microbiota derived 5-MC attenuated particulate induced alveolar epithelial senescence via PI3K/AKT/mTOR pathway modulation, consequently reducing fibrotic pathology. This evidence establishes that PS-MPs initiate pulmonary fibrosis through dysbiosis-mediated metabolic disruption, whereas the microbial metabolite 5-MC counteracts PS-MPs triggered fibrosis by rescuing cellular aging processes.

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