Multi-omics reveals Piezo1-driven pulmonary fibrosis induced by exposure to lithium-ion batteries related metals

, NCM523) has emerged, as a core cathode material, raising growing concerns over its prominent risk of respiratory exposure throughout its entire life cycle. This study established a mouse exposure model via intratracheal instillation to systematically explore the pulmonary toxicity and underlying molecular mechanisms of NCM523 by combining spatial metabolomics, single-cell RNA sequencing (scRNA-seq), and other complementary techniques. The results demonstrated that NCM523 exposure led to significant deposition of Ni, Co, Mn, and Li within mouse lung tissues, inducing restrictive ventilatory dysfunction and pulmonary fibrosis. Spatial metabolomics revealed a significant reduction in essential phospholipids, such as phosphatidylcholine in alveolar injury regions, alongside enrichment of metabolites related to fibroblast activation within fibrotic regions. Meanwhile, scRNA-seq and experimental validation confirmed the induction of the epithelial-mesenchymal transition (EMT) phenotype both in vivo and in vitro. Mechanistically, NCM523 preferentially accumulated as particulates on the plasma membranes of mouse alveolar type II epithelial cells, physically activating the mechanosensitive ion channel Piezo1. This activation triggered calcium influx and endoplasmic reticulum stress (ERS), thereby reducing phospholipid levels and ultimately inducing EMT. Pharmacological inhibition of Piezo1 by GsMTx4 effectively reversed the aforementioned pathological abnormalities, while the agonist Yoda1 exacerbated the damage. And inhibition of Piezo1 could alleviate NCM523-induced pulmonary fibrosis. This study highlighted the critical role of the particulate physical properties in lung injury, clarified Piezo1-mediated mechanotransduction as a central pathway in NCM523-induced pulmonary fibrosis, and provided an important basis for understanding LIBs-related pulmonary fibrosis risks and developing targeted intervention strategies.