Background Ferroptosis is a newly defined form of programmed cell death and is associated with the progression of colorectal cancer (CRC). Abnormal levels of N6-methyladenosine (m6A) modification are frequently identified in CRC, but its regulation of ferroptosis is still unclear. In this study, we report that the m6A modification modulates ferroptotic susceptibility to inhibit CRC progression by targeting m6A-YTHDF2-mediated regulation of MUC1 mRNA stability. Methods CRC cell lines were treated with ferroptosis inducers, and m6A methylation assay kit and dot blot were employed to assess m6A methylation status. Transcriptomic sequencing and immunoprecipitation were employed to elucidate the molecular mechanisms by which m6A modification modulates ferroptotic susceptibility. The CRC mouse tumor models were used to validate the regulatory mechanisms of m6A methylation on ferroptosis in vivo. The CRC patient-derived organoid models (PDOs) were applied to determine the regulatory role of m6A methylation-mediated ferroptosis. Clinical CRC specimens were analyzed to evaluate the relationship between m6A modification and ferroptosis. Results The upregulation of METTL3 and downregulation of FTO enhanced m6A methylation levels, while disruption of m6A methylation conferred resistance to ferroptosis in CRC cells. Mechanistic investigations through transcriptome sequencing and bioinformatics identified MUC1 as a key target for m6A methylation regulation of ferroptosis. YTHDF2 promoted the decay of MUC1 mRNA by recognizing the m6A-binding site at A1078 within 3′UTR regions, which can inhibit the function of SLC7A11 and thereby enhance susceptibility to ferroptosis. Ferroptosis inducer erastin augmented YTHDF2-mediated ferroptotic susceptibility to inhibit the growth of CRC by suppressing MUC1/SLC7A11 signaling in PDOs. Clinically, YTHDF2 was negatively correlated with MUC1 expression in CRC specimens, which was associated with poor prognosis. Conclusions Our findings unveil a crucial mechanism through which YTHDF2 facilitates ferroptotic susceptibility via MUC1 destabilization and subsequent SLC7A11 downregulation. These discoveries open up new possibilities for ferroptosis-regulated therapeutics by offering targets and approaches for the treatment of CRC.

METTL3/FTO drives ferroptosis in colorectal cancer by targeting m⁶A modification of MUC1 mRNA and YTHDF2-dependent SLC7A11/GSH pathway

期刊论文
发表日期：

2026年7月1日

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Zili Zhang,
Kaiwen Cheng,
Yuyao Wei,
Yuqi Sun,
Chun Zhang,
Yang Wu,
Mei Guo

摘要

Background

Ferroptosis is a newly defined form of programmed cell death and is associated with the progression of colorectal cancer (CRC). Abnormal levels of N⁶-methyladenosine (m⁶A) modification are frequently identified in CRC, but its regulation of ferroptosis is still unclear. In this study, we report that the m⁶A modification modulates ferroptotic susceptibility to inhibit CRC progression by targeting m⁶A-YTHDF2-mediated regulation of MUC1 mRNA stability.

Methods

CRC cell lines were treated with ferroptosis inducers, and m⁶A methylation assay kit and dot blot were employed to assess m⁶A methylation status. Transcriptomic sequencing and immunoprecipitation were employed to elucidate the molecular mechanisms by which m⁶A modification modulates ferroptotic susceptibility. The CRC mouse tumor models were used to validate the regulatory mechanisms of m⁶A methylation on ferroptosis in vivo. The CRC patient-derived organoid models (PDOs) were applied to determine the regulatory role of m⁶A methylation-mediated ferroptosis. Clinical CRC specimens were analyzed to evaluate the relationship between m⁶A modification and ferroptosis.

Results

The upregulation of METTL3 and downregulation of FTO enhanced m⁶A methylation levels, while disruption of m⁶A methylation conferred resistance to ferroptosis in CRC cells. Mechanistic investigations through transcriptome sequencing and bioinformatics identified MUC1 as a key target for m⁶A methylation regulation of ferroptosis. YTHDF2 promoted the decay of MUC1 mRNA by recognizing the m⁶A-binding site at A1078 within 3′UTR regions, which can inhibit the function of SLC7A11 and thereby enhance susceptibility to ferroptosis. Ferroptosis inducer erastin augmented YTHDF2-mediated ferroptotic susceptibility to inhibit the growth of CRC by suppressing MUC1/SLC7A11 signaling in PDOs. Clinically, YTHDF2 was negatively correlated with MUC1 expression in CRC specimens, which was associated with poor prognosis.

Conclusions

Our findings unveil a crucial mechanism through which YTHDF2 facilitates ferroptotic susceptibility via MUC1 destabilization and subsequent SLC7A11 downregulation. These discoveries open up new possibilities for ferroptosis-regulated therapeutics by offering targets and approaches for the treatment of CRC.

METTL3/FTO drives ferroptosis in colorectal cancer by targeting m6A modification of MUC1 mRNA and YTHDF2-dependent SLC7A11/GSH pathway

摘要

METTL3/FTO drives ferroptosis in colorectal cancer by targeting m⁶A modification of MUC1 mRNA and YTHDF2-dependent SLC7A11/GSH pathway