METTL3‑mediated m6A methylation and its impact on OTUD1 expression in chronic obstructive pulmonary disease

Gao,Jiameng; Shen,Zheyi; Tian,Weibin; Xia,Junyi; Cao,Weixin; Chen,Zhuoru; Wang,Zhihua; Shen,Yao

doi:10.3892/mmr.2025.13571

METTL3‑mediated m6A methylation and its impact on OTUD1 expression in chronic obstructive pulmonary disease

Authors:
- Jiameng Gao
- Zheyi Shen
- Weibin Tian
- Junyi Xia
- Weixin Cao
- Zhuoru Chen
- Zhihua Wang
- Yao Shen
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Affiliations: Department of Respiratory and Critical Care Medicine, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China, Department of Ultrasound Medicine, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China, College of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Geriatric Medicine, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
Published online on: May 19, 2025 https://doi.org/10.3892/mmr.2025.13571
Article Number: 206
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and chronic inflammation, often exacerbated by cigarette smoke exposure. Ovarian tumor protease domain‑containing protein 1 (OTUD1), a deubiquitinase, has previously been identified as a negative regulator of inflammation through its suppression of NF‑κB signaling. The present study explored the role of OTUD1 in COPD and the regulatory effects of N6‑methyladenosine (m6A) methylation on OTUD1 expression. The expression of OTUD1 in COPD was analyzed using public datasets (GSE38974 and GSE69818). In addition, BEAS‑2B cells were exposed to cigarette smoke extract (CSE) to investigate OTUD1 expression changes. OTUD1 overexpression and knockdown models were also constructed, and the levels of inflammation‑related genes and proteins, inflammatory cytokines and cell pyroptosis were measured using reverse transcription‑quantitative PCR, western blotting, ELISA and flow cytometry. The role of methyltransferase‑like 3 (METTL3)‑mediated m6A methylation in regulating OTUD1 was also examined. Notably, OTUD1 expression was significantly reduced in advanced COPD compared with that in the earlier stage. Furthermore, CSE exposure suppressed OTUD1 expression, which was associated with increased cell pyroptosis and elevated levels of the inflammatory cytokines IL‑1β and IL‑18. OTUD1 overexpression mitigated these effects, indicating its protective role against CSE‑induced cellular damage. Furthermore, METTL3‑mediated m6A methylation inhibited OTUD1 expression, with YTH m6A RNA binding protein 2 (YTHDF2) acting as the reader of this modification. Knockdown of METTL3 or YTHDF2 reduced m6A methylation and restored OTUD1 expression, highlighting a potential mechanism by which cigarette smoke suppresses OTUD1 through enhanced m6A methylation. In conclusion, OTUD1 may serve a protective role in COPD by inhibiting inflammation and reducing cell damage caused by cigarette smoke exposure. The suppression of OTUD1 through METTL3‑mediated m6A methylation and YTHDF2 interaction represents a novel mechanism contributing to COPD pathogenesis, suggesting potential therapeutic targets for mitigating disease progression.

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