METTL3-regulated m6A modification of lncRNA E230001N04Rik is involved in myofibroblast differentiation in arsenic-induced pulmonary fibrosis through promoting senescence of lung epithelial cells.

J Hazard Mater

Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China. Electronic address:

Published: December 2024

Arsenic is a toxic agent that causes respiratory damage. Long non-coding RNAs (lncRNAs) are non-coding transcripts that adsorb specific miRNAs and regulate biological processes of human diseases. N6-Methyladenosine (m6A) is an internal modification of RNAs. However, there are few reports about lncRNAs and m6A modifications as co-regulators of pulmonary fibrosis. For 6 months, C57BL/6 mice were given water containing 0, 10, or 20 ppm arsenite. meRIP-seq and lncRNA-seq analyses showed that the m6A levels of the lncRNA E230001N04Rik were higher, and the levels of E230001N04Rik itself were lower in the high-dose arsenite group than in the controls. Murine lung epithelial 12 (MLE12) cells, exposed to 8 μM arsenite for 8 passages, had elevated METTL3 and miR-20b-3p and low E230001N04Rik. Arsenite induced cellular senescence, as demonstrated by secretion of factors related to the senescence-associated secretory phenotype (SASP). Arsenite-treated MLE12 cells co-cultured with primary lung fibroblasts (PLFs) caused myofibroblast differentiation. These data show that METTL3 reduces E230001N04Rik expression via controlling its m6A levels, which regulate miR-20b-3p and mediate the senescence of alveolar epithelial cells (AECs). Thereby, E230001N04Rik is involved in the arsenite-induced myofibroblast differentiation and in pulmonary fibrosis. These observations provide a prospective mechanism for chronic pulmonary disease caused by arsenite.

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http://dx.doi.org/10.1016/j.jhazmat.2024.136094DOI Listing

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