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Background <p>Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by persistent airflow obstruction. Studies have shown that Lipocalin 2 (LCN2) and Methyltransferase-like protein 3 (METTL3) are involved in COPD progression. However, whether LCN2 and METTL3 jointly regulate the progression of COPD and the molecular mechanism are still unclear.</p> Methods <p>Human lung microvascular endothelial cells (HMVECs) were treated with Cigarette smoke extract (CSE) to construct an in vitro cell model of COPD. Then, cell viability and apoptosis were detected by CCK-8 and flow cytometry. Meanwhile, the levels of IL-6, TNF-α, ROS, Fe<sup>2+</sup>, MDA, and GSH were measured by ELISA and the corresponding kits. Bioinformatics analysis was used to predict the m6A methylation modification sites on LCN2 mRNA. Besides, the methylation modification level of LCN2 was monitored by MeRIP. The binding of METTL3 and IGF2BP3 to LCN2 was verified by RIP. And the stability of LCN2 mRNA was analyzed by actinomycin D. The role of LCN2 in COPD in vivo model was verified by constructing an in vivo mouse model.</p> Results <p>Silencing LCN2 could effectively reduce CSE induced HMVECs injury and ferroptosis. METTL3 stabilized LCN2 expression through m6A methylation. IGF2BP3 could bind to LCN2 and stabilize its expression. METTL3 inhibitor STM2457 could restore CSE induced HMVEC injury and ferroptosis. Additionally, overexpression of LCN2 could also reverse the effect of METTL3 silencing on CSE-induced HMVEC injury. METTL3 inhibited the NRF2/SLC7A11/GPX4 pathway by stabilizing LCN2. Moreover, knockdown of LCN2 alleviated lung injury and inflammatory response in COPD mice and activate NRF2/SLC7A11/GPX4 signaling pathway.</p> Conclusion <p>This study confirmed that METTL3/IGF2BP3 enhanced the stability of LCN2 and hindered the NRF2/SLC7A11/GPX4 pathway through m6A methylation modification, thereby aggravating the progression of COPD. It provides a new direction for the study of the mechanism of COPD, identifies key molecules such as METTL3 and IGF2BP3, and lays a foundation for the development of COPD treatment strategies targeting m6A modification or NRF2 pathway.</p>

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METTL3 mediates m6A methylation of LCN2 through IGF2BP3 to promote ferroptosis in chronic obstructive pulmonary disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月26日

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  • Fang Chen,
  • Dan Liu,
  • Zuoquan Zhu,
  • Da Chen

摘要

Background

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by persistent airflow obstruction. Studies have shown that Lipocalin 2 (LCN2) and Methyltransferase-like protein 3 (METTL3) are involved in COPD progression. However, whether LCN2 and METTL3 jointly regulate the progression of COPD and the molecular mechanism are still unclear.

Methods

Human lung microvascular endothelial cells (HMVECs) were treated with Cigarette smoke extract (CSE) to construct an in vitro cell model of COPD. Then, cell viability and apoptosis were detected by CCK-8 and flow cytometry. Meanwhile, the levels of IL-6, TNF-α, ROS, Fe2+, MDA, and GSH were measured by ELISA and the corresponding kits. Bioinformatics analysis was used to predict the m6A methylation modification sites on LCN2 mRNA. Besides, the methylation modification level of LCN2 was monitored by MeRIP. The binding of METTL3 and IGF2BP3 to LCN2 was verified by RIP. And the stability of LCN2 mRNA was analyzed by actinomycin D. The role of LCN2 in COPD in vivo model was verified by constructing an in vivo mouse model.

Results

Silencing LCN2 could effectively reduce CSE induced HMVECs injury and ferroptosis. METTL3 stabilized LCN2 expression through m6A methylation. IGF2BP3 could bind to LCN2 and stabilize its expression. METTL3 inhibitor STM2457 could restore CSE induced HMVEC injury and ferroptosis. Additionally, overexpression of LCN2 could also reverse the effect of METTL3 silencing on CSE-induced HMVEC injury. METTL3 inhibited the NRF2/SLC7A11/GPX4 pathway by stabilizing LCN2. Moreover, knockdown of LCN2 alleviated lung injury and inflammatory response in COPD mice and activate NRF2/SLC7A11/GPX4 signaling pathway.

Conclusion

This study confirmed that METTL3/IGF2BP3 enhanced the stability of LCN2 and hindered the NRF2/SLC7A11/GPX4 pathway through m6A methylation modification, thereby aggravating the progression of COPD. It provides a new direction for the study of the mechanism of COPD, identifies key molecules such as METTL3 and IGF2BP3, and lays a foundation for the development of COPD treatment strategies targeting m6A modification or NRF2 pathway.