Table 7 Epigenetic modification of Ferroptosis by m⁶A in cancer

NSCLC

m⁶A

FSP1

METLL3

-

-

Exosomal miR-4443 promotes cisplatin resistance by enhancing METLL3-mediated m⁶A modification of FSP1, thereby inhibiting ferroptosis

²¹⁶

NSCLC

m⁶A

SLC7A11

-

-

YTHDC2

YTHDC2 inhibit LUAD tumorigenesis by suppressing SLC7A11 mRNA and promoting its decay in an m⁶A-dependent manner

²¹⁷

NSCLC

m⁶A

HOXA13

YTHDC2

YTHDC2 promote m⁶A methylation and subsequent destabilization of HOXA13 mRNA to suppress SLC3A2, thereby inducing ferroptosis and inhibiting LUAD tumorigenesis

²¹⁸

NSCLC

m⁶A

GPX4;SLC3A2;FTH1;ACSL3

METTL3

-

IGF2BP3

Upregulated IGF2BP3 recognizes and binds target mRNAs encoding anti-ferroptosis factors that can be m⁶A-methylated by METTL3, leading to suppress ferroptosis and stimulate tumorigenesis.

²¹⁹

NSCLC

m⁶A

SLC7A11

METTL3

-

YTHDF1

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m⁶A modifcation

²²⁰

HCC

m⁶A

FSP1

-

-

YTHDF2

Elevated HDLBP inhibited the ferroptosis. HDLBP bound to and stabilized the lncFAL. The splicing of lncFAL was increased by YTHDF2 in a m⁶A-dependent manner. lncFAL reduced ferroptosis vulnerability by directly binding to FSP1 and competitively abolishing Trim69-dependent FSP1 polyubiquitination degradation.

¹³³

HCC

m⁶A

Nrf2

-

-

IGF2BP3

Upregulation of IGF2BP3 inhibit sorafenib-induced ferroptosisis through promoting Nrf2 mRNA stability in an m⁶A-dependent manner

²²¹

HCC

m⁶A

SLC7A11

METTL3

-

IGF2BP1

METTL3-mediated SLC7A11 m⁶A modification enhances HB ferroptosis resistance. The METTL3/IGF2BP1/m⁶A modification promotes SLC7A11 mRNA stability and upregulates its expression by inhibiting the deadenylation process.

²²²

Thyroid cancer

m⁶A

TIAM1/Nrf2

-

ALKBH5

-

ALKBH5 inhibits thyroid cancer progression by promoting ferroptosis through inactivating Nrf2 by decreasing the m⁶A level of TIAM1 expression through m⁶A modification.

²²³

Thyroid cancer

m⁶A

SLC7A11

-

FTO

-

FTO prevents thyroid cancer progression by downregulating SLC7A11 by m⁶A methylation in a ferroptosis-dependent manner

²²⁴

BC

m⁶A

GPX4

METTL16

-

-

METTL16 epigenetically enhances GPX4 expression via m⁶A modification to promote breast cancer progression by inhibiting ferroptosis

²²⁵

BC

m⁶A

FGFR4

METTL14

YTHDC2

m⁶A modification level is reduced due to the downregulation of METTL14 in anti-HER2 resistant breast cancer. Decrease of m⁶A level prevents the YTHDC2 mediated FGFR4 mRNA degradation, therefore, lead to the accumulation of FGFR4 in resistant breast cancer. FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to increase the transcription of the SLC7A11 and FPN1 gene. Upregulated SLC7A11 and FPN1 accelerates glutathione synthesis and Fe²⁺ efflux, which confer anti-HER2 resistance by attenuating ferroptosis in breast cancer. Roblitinib, a highly selective inhibitor of FGFR4, overcomes anti-HER2 resistance by triggering ferroptosis in recalcitrant HER2-positive breast cancer.

²²⁶

GBM

m⁶A

SLC7A11

METTL3

-

-

NKAP inhibit ferroptosis by recruiting SFPQ to promote SLC7A11 mRNA splicing in an METTL3-mediated m⁶A-dependent manner.

²²⁷

NPC

m⁶A

OTUB1

-

FTO

-

Upregulated FTO enhances radioresistance by repressing radiation-induced ferroptosis in NPC. FTO acts as an m⁶A demethylase to erase the m⁶A modification of the OTUB1 transcript and promote the expression of OTUB1, thereby inhibiting the ferroptosis.

²²⁸

HPSCC

m⁶A

Nrf2

-

ALKBH5

IGF2BP2

ALKBH5 inhibits ferroptosis by posttranscriptionally activating Nrf2 in an m⁶A-IGF2BP2-dependent manner.

²²⁹

GC

m⁶A

CBS

-

-

YTHDF2

HIF-1α induces lncRNA-CBSLR to recruit YTHDF2 protein and CBS mRNA to form CBSLR/ YTHDF2/CBS complex, which in turn decreases CBS mRNA stability in an m⁶A dependent manner, leading to reduce methylation of ACSL4 protein, thus, the protein is degraded via the ubiquitination-proteasome pathway, thereby inhibit ferroptosis.

²³⁰