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. 2025 Jul 16.
doi: 10.1007/s00210-025-04207-7. Online ahead of print.

The METTL3/IGF2BP1 axis-mediated m6 A modification of TRIM11 mRNA suppresses ferroptosis and accelerates malignant progression in non-small cell lung cancer cells by degrading ACSL4

Haiyang Chen  1   2 , Chunmei Wang  2 , Heyang Dai  2 , Jian Shi  3
Affiliations

The METTL3/IGF2BP1 axis-mediated m6 A modification of TRIM11 mRNA suppresses ferroptosis and accelerates malignant progression in non-small cell lung cancer cells by degrading ACSL4

Haiyang Chen et al. Naunyn Schmiedebergs Arch Pharmacol. .

Abstract

Tripartite motif-containing motif 11 (TRIM11) possesses a pro-tumorigenic properties in non-small cell lung cancer (NSCLC). However, the determinants that drive TRIM11 dysregulation remains to be uncovered. Effect on cell functions was assessed by detecting cell apoptosis, proliferation, viability, ferroptosis, and invasive and migratory capacities. Evaluation of in vivo activity was performed using mouse xenograft studies. Relationship between TRIM11 and METTL3 or IGF2BP1 was predicted by bioinformatics and confirmed by RNA immunoprecipitation experiments or luciferase assays. The regulation of TRIM11 in ACSL4 protein was tested by IP experiment and protein stability analysis. TRIM11 was overexpressed in NSCLC, and its high expression tended to result in poor prognosis and enhanced tumor grade. Functionally, TRIM11 disruption suppresses the malignant progression of NSCLC cells by promoting cancer cell apoptosis and ferroptosis and repressing invasion, proliferation, and migration. Mechanistically, METTL3 enhances m6A modification of TRIM11 mRNA via an IGF2BP1/m6A manner. Inhibition of METTL3 reduced TRIM11 to promote NSCLC cell ferroptosis and suppress malignant progression in vitro, as well as to mediate xenograft growth inhibition in vivo. Additionally, TRIM11 degraded ACSL4 through K63-linked ubiquitination to affect the malignant progression and ferroptosis of NSCLC cells. These findings indicate that the METTL3/IGF2BP1 axis-mediated m6A methylation of TRIM11 mRNA is responsible for NSCLC malignant progression of NSCLC. Our study is instrumental for the development of TRIM11-basic therapies for NSCLC.

Keywords: Ferroptosis; M6 A modification; Malignant progression; NSCLC; TRIM11.

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Conflict of interest statement

Declarations. Ethics approval: Collection of human specimens was conducted under a protocol approved by Cangzhou People’s Hospital Ethics Committee. All mouse work was carried out following the National animal experiment guidelines and approved protocols from the Fourth Hospital of Hebei Medical University Animal Care and Use Committee. Consent to participate: Not applicable. Competing interests: The authors declare no competing interests.

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