The methylation of m⁶A is catalyzed by a multicomponent methyltransferase complex, which is mediated by the methyltransferase complex (MTC). The first characteristic component of the m⁶A methyltransferase complex is METTL3, an S-adenosyl-methionine (SAM) binding protein (Bokar et al., 1997). Another active component of the m⁶A methyltransferase complex, METTL14, co-localizes with METTL3 in the nuclear speckle and forms a stable heterogeneous complex in a 1:1 ratio with METTL3 (Liu et al., 2014). WTAP (Wilms tumor 1-associated protein) is the complex’s third key component (Wang et al., 2016). RBM15 and its analog RBM15B were later discovered to be members of a complex that facilitates their recruitment to specific sites on RNA molecules (Patil et al., 2016). Recently, researchers have identified vir-like m⁶A methyltransferase-associated proteins VIRMA (also known as KIAA1429), HAKAI and zinc finger protein 13 (ZC3H13) to interact with other components of the complex to form a large multi-component complex (Yue et al., 2018). In addition to this, METTL16, a homolog of METTL3, is thought to be a regulator of cellular SAM levels (Zhang et al., 2019). It can catalyze m⁶A modification in small nuclear RNAs, U6 snRNAs, and other non-coding RNAs (lncRNAs) (Warda et al., 2017). METTL5 has a similar function (van Tran et al., 2019) (Figure 1).

In 2011, the first m⁶A demethylase, Fat mass and obesity-associated protein (FTO) were identified, indicating that m⁶A RNA methylation is reversible and dynamic (Jia et al., 2011). A second RNA demethylase, α-ketoglutarate-dependent dioxygenase homolog 5 (ALKBH5), which is predominantly expressed in the testis, was soon discovered in 2013 (Zheng et al., 2013; Ueda et al., 2017). The recently discovered demethylase ALKBH3, which appears to demethylate tRNA preferentially, is also commonly thought to be a DNA repair enzyme (Beharry et al., 2016) (Figure 1).

The m⁶A methylation recognition protein activates downstream signaling pathways by selectively recognizing bases where m⁶A modifications occur, which regulates mRNA export, translation, metabolism, and stability. The m⁶A methylation recognition proteins can be broadly classified according to their functions: YTHDF2, YTHDF3, and YTHDC2, which promote mRNA degradation; IGF2BP1/2/3, which maintain mRNA stability; and YTHDF1, YTHDF3, YTHDC2 and IGF2BP1/2/3, which promote translation of target mRNAs(Huang et al., 2018); YTHDC1, on the other hand, may affect mRNA splicing and export from the nucleus (Wang et al., 2014). Members of the heterogeneous nuclear ribonucleoprotein (HNRNP) family (HNRNPA2B1, HNRNPC and HNRNPG) are potential m⁶A methylation recognition proteins that play a crucial role in regulating the processing and maturation of RNA substrates and gene expression (Lin et al., 2016). In addition, METTL3 in the cytoplasm can act as a reader protein and promote the translation of certain specific cellular mRNA types (Alarcon et al., 2015). Eukaryotic initiation factor 3 (EIF3), proline-rich coiled-coil protein 2A (PRRC2A), and other recognition proteins have also been reported (Wu et al., 2019) (Figure 1).

As a widely distributed RNA modification with many recognition proteins, m⁶A mediates various biological functions involved in the regulation of mRNAs, the direction of differentiation of stem cells, the regulation of development, the development of neurological diseases and the progression of tumors.

RNA m⁶A modification appears to be transcription-independent. However, a recent study revealed that chromosome-associated regulatory RNAs (carRNAs), can be modified by m⁶A to cause carRNA attenuation via YTHDC1, influencing chromatin state and downstream transcription (Liu et al., 2020). In mammals, m⁶A modifications can regulate the pathway of pre-mRNA splicing. For example, the m⁶A recognition protein HNRNPG may interact with RNA polymerase II and nascent pre-mRNA co-transcription using the Arg-Gly-Gly motif to control selective splicing (Zhou et al., 2019). Additionally, YTHDC1 can direct pre-mRNA splicing factors to bind to certain mRNAs and regulate mRNA splicing (Xiao et al., 2016). There is also evidence that m⁶A can alter RNA structure and thus affect RNA-protein interactions in cells. In addition, it was found that m⁶A is involved in regulating biological development and plays a vital role in sex determination (Haussmann et al., 2016), spermatogenesis (Xu et al., 2017), epithelial cell differentiation (Wang et al., 2017) and other functions (Huang et al., 2020).

According to a study, lung cancer patient’s circulating tumor cells (CTCs) of considerably increased the m⁶A modification. This suggests that upregulating the m⁶A RNA methylation in CTCs may assist monitor and preventing tumor spread (Huang et al., 2016). In addition, R-2HG exhibited anti-leukemic effects as it increased m⁶A modification in sensitive cells by inhibiting FTO proteins (Su et al., 2018). Not coincidentally, the modification of m⁶A regulators in cancer has also been reported. Investigators found that METTL3 was modified by SUMO1, and significantly inhibited its m⁶A methyltransferase activity, resulting in reduced m⁶A levels in mRNA. These results suggest that modifying m⁶A regulators may be a novel molecular mechanism for regulating m⁶A methylation (Du et al., 2018).

Ferroptosis is a regulated form of cell death characterized by accumulating iron-mediated lipid peroxidation of polyunsaturated fatty acid (PUFA) to lethal levels. Sensitivity to ferroptosis is closely related to many biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism (Stockwell et al., 2017). Current studies have shown that the accumulation of PUFA oxide is a marker of ferroptosis. Its accumulation process mainly involves deoxygenation inhibition (mainly GPX4 and ferroptosis suppressor protein 1 (FSP1)) and enhanced peroxidation catalyzed by iron and a series of enzymes. A detailed diagram is shown in Figure 2.

Among the amino acid metabolism pathways, the regulatory systems involved in ferroptosis are mainly the Xc⁻ system (SLC7A11/SLC3A2 complex) and the lipid repair enzyme glutathione peroxidase 4 (GPX4) system (Ursini and Maiorino, 2020). When the Xc⁻ system is inhibited, cystine uptake decreases and so does the amount of glutathione (GSH), leading to the accumulation of lipid radicals. After GPX4 inactivation, lipid radicals are converted to toxic lipid peroxides catalyzed by iron, which leads to the rupture of PUFA of cell membrane lipids and induces ferroptosis (Doll and Conrad, 2017). Therefore, when the cystine transport protein (Erastin) is inhibited, intracellular GSH is depleted, which eventually leads to the inactivation of GPX4, leading to the accumulation of lipid peroxidation, which can induce cell death. Inhibition of GPX4 enzymes, such as RSL3, can also directly contribute to this effect. Therefore, inhibition of Xc⁻ system, insufficient or depleted GSH synthesis, and inactivation of GPX4 all lead to the accumulation of lipid peroxides in the cell, and ultimately to ferroptosis (Cao et al., 2022).

In the lipid metabolism pathway, arachidonic acid (AA) and adrenaline (AdA) can be esterified by acyl-CoA synthetase long-chain family member 4 (ACSL4) to lipid coenzyme a derivatives, and then recombinant lysophosphatidyl-choline acyltransferase 3 (LPCAT3) promotes the incorporation of PUFA into phospholipids to form polyunsaturated fatty acid phospholipids (PUFA-PL) (Yang et al., 2016; Doll et al., 2017). PUFA-PLs are susceptible to oxidation triggered by free radicals mediated by lipoxygenases (LOXs). This oxidation eventually disrupts the lipid bilayer and affects membrane function, thereby promoting ferroptosis (Wu et al., 2019). Thus, activation of ACSL4, LPCAT3, and LOXs leads to excessive lipid peroxidation, resulting in the development of ferroptosis.

Among the pathways associated with iron metabolism, Fe³⁺ enters the blood and binds to transferrin (TF) to form TF-Fe³⁺, which binds to the transferrin receptor (TFRC) on the cell surface. The intracellular metal reductase STEAP3 reduces Fe³⁺ to Fe²⁺ and then releases Fe²⁺ into the dynamic iron pool of the cytoplasm via divalent metal transporter protein 1 (DMT1) (Gao et al., 2015). Under pathological conditions, Fe²⁺ accumulates in the cell. It undergoes the Fenton reaction, generating a large amount of ROS, which will generate lipid peroxides by a series of peroxidation reactions with PUFA on the cell membrane, leading to the destruction of the cell membrane structure and eventually causing ferroptosis (Yu et al., 2019).

Other factors that affect ferroptosis sensitivity include coenzyme Q10 (CoQ10) (Bersuker et al., 2019), reduced coenzyme II (Nicotinamide Adenine Dinucleotide phosphate, NADPH) (Guo et al., 2020), selenium (Alim et al., 2019), p53 (Jiang et al., 2015)., nuclear factor E2-related factor 2 (NRF2) (Sun et al., 2016), and Vitamin E (Imai et al., 2017).

Susceptibility to ferroptosis is tied to many biological processes, and excess iron can lead to tissue damage and an increased risk of cancer. It has also been associated with pathological cell death associated with mammalian neurodegenerative diseases (such as Alzheimer’s disease, Huntington’s chorea and Parkinson’s syndrome), stroke, cerebral hemorrhage, traumatic brain injury, local ischemia-reperfusion injury and renal failure (Jiang et al., 2021). In addition, ferroptosis is a potential weapon against the development of many cancers, such as colorectal (Liu et al., 2022b), pancreatic (Yamaguchi et al., 2018), gastric (Zhang et al., 2020), lung (Wang et al., 2019), liver (Capelletti et al., 2020), renal cell (Yang et al., 2019) and ovarian (Wang et al., 2021) cancers.

Compared with normal cells, cancer cells are more metabolically active, with dysfunctional mitochondria and more ROS accumulation, which increases the sensitivity of cancer cells to ferroptosis. Tumors are more sensitive to ferroptosis induction, namely, when they undergo epithelial-mesenchymal transition or when they acquire “stemness” and become tumor stem cells (Zhang et al., 2018). In brief, induction of ferroptosis may not only be a new means of inhibiting tumor cell growth, but also provides a new promising pathway for reversing tumor drug resistance.

Meanwhile, several studies have demonstrated the role of ferroptosis in neurodegenerative and cardiovascular diseases, suggesting the therapeutic potential of ferroptosis inhibition. Iron chelators have been tested in different experimental systems for stroke and neurodegeneration (Hambright et al., 2017). Elevated iron levels have been detected in patients with aging and degenerative diseases such as Parkinson’s disease (PD), Huntington’s disease and Alzheimer’s disease (AD) (Buijs et al., 2017). Multiple lines of evidence suggest that the GSH-GPX4 antioxidant pathway is significantly abnormal in both AD and PD patients and that using antioxidant drugs may alleviate symptoms of AD and PD pathology (Yan et al., 2021).

The exogenous pathway enables initiation by inhibition of cell membrane transport proteins such as cystine/glutamate reverse transporter proteins (Xc⁻ system), or activation of iron transport proteins. Increasing iron uptake, decreasing iron storage and limiting iron efflux lead to increased iron accumulation, which then promotes ferroptosis through a series of signaling pathways.

In a recent study, high expression of YTHDC2 was found to induce ferroptosis in lung adenocarcinoma (LUAD) cells. SLC7A11 mRNA is modified by m⁶A and binds to YTHDC2 to inhibit the antioxidant function of LUAD cells by accelerating the decay of SLC7A11 mRNA (Ma et al., 2021a). Another subunit of the Xc⁻ system, SLC3A2, is equally essential for YTHDC2-induced ferroptosis. HOXA13 acts as a transcription factor to stimulate the expression of SLC3A2. Thus, YTHDC2 inhibits SLC3A2 by repressing HOXA13 indirectly through m⁶A (Ma et al., 2021b). Similarly, METTL3-mediated m⁶A modification stabilizes SLC7A11 mRNA and promotes its translation, thereby promoting LUAD cell proliferation and inhibiting ferroptosis. This is because the m⁶A reader YTHDF1 is recruited by METTL3 to enhance the modification of SLC7A11 m⁶A (Xu et al., 2022). Not coincidentally, in the modification of SLC7A11 by METTL3, IGF2BP1 promoted the stability of SLC7A11 mRNA and upregulated its expression by inhibiting the process of demethylation thereby suppressing the sensitivity of hepatoblastoma to ferroptosis before leading to disease progression (Liu et al., 2022a). Exogenous overexpression of NKAP protects glioblastoma cells from ferroptosis by positively regulating SLC7A11, promoting cell resistance to ferroptosis inducers (Alarcon et al., 2015).

As an m⁶A demethylase, FTO downregulates SLC7A11 through m⁶A demethylation, regulating ferroptosis in papillary thyroid carcinoma (PTC), thereby inhibiting the development of PTC (Ji et al., 2022). FTO removes m⁶A modification of OTUB1 transcripts and promotes the expression of OTUB1. By stabilizing the interaction between OTUB1 and SLC7A11, FTO inhibits radiation-induced cell ferroptosis and ultimately triggers radiotherapy resistance in nasopharyngeal carcinoma (Huang et al., 2023). ALKBH5 eliminated the m⁶A modification on SLC7A11 mRNA, reduced the stability of SLC7A11 mRNA, and further reduced the expression of SLC7A11, thus promoting ferroptosis in CRC cells (Luo et al., 2023). Using drugs to induce ferroptosis is a popular strategy. Curdione activates ferroptosis by enhancing MELL14 and the methylation of SLC7A11 mRNA and HOXA13 mRNA, reducing the stability of the reading protein YTHDF2, leading to the expression of SLC3A2. These results provide references or new ideas for the study of ferroptosis in colorectal cancer (Wang et al., 2023). Inhibition of METTL14 is triggered in an HIF-1α-dependent manner under hypoxia conditions, and SLC7A11 was found to be a direct target of METTL14. METTL14 induces m⁶A modification of SLC7A11 mRNA at 5′UTR, and its degradation depends on a YTHDF2-dependent pathway, which can effectively eliminate ferroptosis in HCC cells (Fan et al., 2021). At the same time, a potential m⁶A modification site on SLC7A11 mRNA was also found in another study, and YTHDF2 can bind to SLC7A11 mRNA in an m⁶A dependent manner. YTHDF2 promotes the degradation of SLC7A11 mRNA, thereby reducing its mRNA stability. Therefore, YTHDF2 accelerates the ferroptosis of endothelial cells in cerebrovascular atherosclerosis (Li et al., 2023). KIAA1429, a key component of the m⁶A methyltransferase complex, targets SLC7A11 during ferroptosis in Hepatocellular carcinoma (HCC) cells. It protects HCC cells against ferroptosis and provides a new insight into abnormally regulated external transcriptomics in the HCC context (Wang et al., 2023). The resulting discovery of a vital role for m⁶A modification in Xc⁻system-mediated ferroptosis provides a potential strategy for treating the disease by blocking the m⁶A- Xc⁻ system axis.

ACSL4 is a member of the long chain family of acyl-CoA synthetase proteins and is one of the core factors of lipid peroxidation during ferroptosis after myocardial I/R injury. Inhibition of ACSL4 can prevent ferroptosis and reduce myocardial and kidney I/R damage (Qiu et al., 2023). The LPCAT3 protein can also interact with ACSL4, and its upregulation inhibits the expression of ACSL4. In vitro models, ACSL4 was identified as a target for LPCAT3 to inhibit mitochondrial damage. Methylation regulation of LPCAT3 improves osteoarthritis by regulating ACSL4 to inhibit chondrocyte ferroptosis (Habaxi et al., 2024).

The transferrin receptor (TFRC) is essential for the uptake of the transferrin - iron complex into cells. It has been shown that in head and neck squamous cell carcinomas (HNSCCs), the YTH structural domain of the m⁶A reader YTHDF1 interacts with the 3′UTR and 5′UTR of TFRC mRNA. It positively regulates the translation of m⁶A-modified TFRC mRNA. The high expression of YTHDF1 may increase iron metabolism by promoting the accumulation of intratumoral iron (Jung et al., 2019). From a therapeutic perspective, targeting YTHDF1 and TFRC-mediated iron metabolism to promote iron homeostasis imbalance may be a promising strategy for treating HNSCC. Meanwhile, upregulation of METTL3 lactation enhanced the stability and expression level of METTL3 protein in hemin-treated PC12 cells. After METTL3 silencing, the occurrence of ferroptosis can be inhibited by regulating the m⁶A level of TFRC mRNA, which is a method to treat cerebral hemorrhage (Zhang et al., 2023).

Ferritin (FTH) is a key regulator of ferroptosis. Downregulated YTHDF1 inhibited cell proliferation, migration and invasion. FTH has been identified as a key target for YTHDF1. In addition, overexpression in YTHDF1 deficient cells partially restored the inhibition. Thus, YTHDF1 upregulation promotes lung cancer by accelerating ferritin translation in an m⁶A-dependent manner (Diao et al., 2023). Other studies have shown that LncRNA CACNA1G-AS1 can upregulate the expression of FTH1 through the IGF2BP1 axis, thereby inhibiting ferroptosis by regulating FTH phagocytosis, and ultimately promoting the proliferation and migration of ovarian cancer cells (Jin et al., 2023).

FSP1 is a necessary ferroptosis inhibitor. High levels of miR-4443 inhibit cisplatin induced tumor death by reducing the expression level of METTL3 and increasing the level of FSP1, suggesting that miR-4443 plays an important role in cisplatin resistance in NSCLC through the METTL3/FSP1 mediated ferroptosis (Song et al., 2021). Downregulation of YTHDC1 promotes lung tumor progression and leads to ferroptosis resistance through m⁶A mediated upregulation of FSP1 protein levels, providing a treatment option for lung cancer with high YTHDC1 levels associated with ferroptosis (Yuan et al., 2023). The upregulation of METTL3 and FSP1 induced by fear stress increases the m⁶A level of glioma tumor tissue, providing a new understanding of glioma development by inhibiting the tumor progression caused by ferroptosis (Bu et al., 2023).

NRF2 plays a crucial role in the regulation of cellular antioxidant molecules. It has been reported that there is a significant m⁶A modification site on the 3′UTR, and WTAP can install its methylation. In addition, YTHDF1 identifies the m⁶A site on NRF2 mRNA and enhances its mRNA stability, thereby accelerating the progression of bladder cancer malignancies (Wang et al., 2023). In another study, the action mechanism and detailed mechanism of SNAI3-AS1/SND1/NRF2 in glioma ferroptosis were elucidated. lncRNA SNAI3-AS1 interfered with SND1’s m⁶A recognition of NRF2 mRNA, thereby reducing the stability of NRF2 mRNA and promoting the occurrence of ferroptosis (Zheng et al., 2023). NRF2 has also been found to be a target of FTO, which demethylates m⁶A in NRF2 mRNA, thereby impairs the stability of NRF2 mRNA. Therefore, the results of this study illustrate the important role of FTO in Parkinson’s disease (PD) through the ferroptosis (Pang et al., 2024).

p53 can inhibit cystine uptake by down-regulating the expression of SLC7A11, thereby inducing ferroptosis. Erianin significantly increased the m⁶A modification level of the 3′UTR of ALOX12 and P53 mRNA in Human renal cancer stem cells (HuRCSCs). By promoting modification of m⁶A, kidney cancer stem cells can be induced by ferroptosis, and finally have therapeutic effect (Shen et al., 2023). Silencing KIAA1429 promoted erastin -induced NSCLC cell ferroptosis, activated the p53 signaling pathway, and inhibited its proliferation, migration, and invasion. This also suggests that m⁶A may be a molecular target for a promising therapeutic strategy for the treatment of NSCLC (Wu et al., 2023).

The endogenous pathway is activated by blocking intracellular antioxidant enzymes (e.g., GPX4). Lipid peroxide accumulation is a marker of ferroptosis, GPX4 reduces cytotoxic lipid peroxides (L-OOH) to the corresponding alcohol (L-OH), and inhibition of GPX4 activity leads to the accumulation of cell membrane lipid peroxides (Conrad and Pratt, 2019). Studies have shown that FTO can directly regulate the m⁶A modification of GPX4 mRNA at site 193, while YTHDF2 regulates AKT inhibitation-induced ferroptosis by recognizing and degrading the m⁶A methylation modification site on GPX4 mRNA (Zhang et al., 2023). RUNX1-IT1 can directly bind to IGF2BP1, resulting in IGF2BP1 occupying more of GPX4 mRNA and increasing the stability of GPX4 mRNA. Targeting the previously unappreciated RUNX1-IT1/IGF2BP1/GPX4 regulatory axis may be a promising treatment for breast cancer patients (Wang et al., 2023). METTL16 epigenetically enhances GPX4 expression through m⁶A modification and promotes breast cancer progression by inhibiting ferroptosis (Ye et al., 2023). By demethylating the m⁶A modification of ACSL3 and GPX4 mRNA, FTO reduces its stability and inhibits the expression of ACSL3 and GPX4. Ferroptosis activation of high levels of FTO in Oral squamous cell carcinoma (OSCC) may be a potential therapeutic target (Wang et al., 2023) found that METTL3 was involved in high glucose and palmitic acid (HGPA)-induced osteoporosis through upregulation of the ASK1/p38 signaling pathway, and that activation of the ASK1/p38 pathway was associated with ferroptosis induction. This study suggests that high glucose and high fat (HGHF) induces ferroptosis in diabetic osteoporosis by activating the METTL3/ASK1-p38 pathway (Lin et al., 2022).

Tumors are the number one problem in the world, and in the treatment of oncological diseases, the most crucial purpose of m⁶A involvement in the biology of ferroptosis is to promote the occurrence of ferroptosis in tumor cells. Combined with the above description, the effect of eliminating malignant tumors can be achieved by activating the metabolic pathway of ferroptosis. For example, both subunits of the Xc⁻system in the development of lung adenocarcinoma are indispensable for YTHDC2 induced ferroptosis (Ma et al., 2021b).

In addition, METTL3-mediated m⁶A modification can stabilize SLC7A11 mRNA and promote its translation, thereby promoting the proliferation of LUAD cells and inhibiting ferroptosis. Down-regulating METTL3 can inhibit this process (Xu et al., 2022). Similarly, miR-30c-5p promotes the ferroptosis of cervical cancer by targeting the METTL3/KRAS axis, and inhibits the growth and metastasis of xenografts of cervical cancer. Targeting this process can be effectively treated (Gong et al., 2024).

WTAP-mediated m⁶A modification on circCMTM3 inhibits ferroptosis in hepatocellular carcinoma by recruiting IGF2BP1 to increase PARK7 stability (Chen et al., 2023). WTAP also can regulate NUPR1 m⁶A modification to upregulate LCN2, thereby promoting the proliferation, migration and invasion of breast cancer (Tan et al., 2023). Meanwhile, WTAP accelerates bladder cancer malignancy by targeting NRF2 through YTHDF1-m⁶A dependent ferroptosis regulation (Wang et al., 2023). Each of these pathways can play a therapeutic role by inhibiting WTAP.

One study found that ALKBH5 leads to impaired stability of NFE2L2/NRF2 mRNA and reduced expression in hypopharyngeal squamous cell carcinoma (HPSCC) through an m⁶A-IGF2BP2-dependent mechanism. Therefore, ferroptosis as an anti-cancer treatment may help treat HPSCC patients with high ALKBH5 expression (Ye et al., 2022). EGFR blocks the nuclear output of ALKBH5, increases the clearance function of m⁶A, and protects glioblastoma from ferroptosis by producing GSH. ALKBH5 inhibitors enhance the antitumor efficacy of EGFR or GSH inhibitors (Lv et al., 2023). However, ALKBH5 expression is decreased in thyroid cancer, and ferroptosis can be induced by overexpression of ALKBH5 along the m⁶A-TIAM1-NRF2/HO-1 axis, thereby inhibiting the progression of thyroid cancer, suggesting that ALKBH5 may be a potential target molecule for the treatment and diagnosis of thyroid cancer (Li et al., 2023). In contrast, in studies of nanoengineering for disease, black phosphorus quantum dots (BPQDs) significantly increased m⁶A levels and decreased levels of the demethylase ALKBH5 in lung cells. YTHDF2 recognizes these m⁶A-modified mRNAs, which leads to their decay in the cytoplasm. Ultimately, ferroptosis is triggered by biological processes including mitochondrial dysfunction, lipid peroxidation and iron overload (Ruan et al., 2021).

DHA treatment increased autophagy levels in HSCs, and upregulated m⁶A modification was essential for DHA to activate autophagy by reducing FTO (Shen et al., 2022). It ultimately plays an anti-fibrotic role by inhibiting the activation of hematopoietic stem cells (Shen et al., 2021). Self-assembled FTO inhibitor-loaded GSH bioimprinted nanocomposites (GNPIPP12MA) enhance improved GSH depletion and enhanced anti-leukemic chemo-immunotherapy. GNPIPP12MA selectively targets AML cells in the myeloid ecotone and induces ferroptosis by depleting intracellular GSH to achieve a therapeutic effect (Cao et al., 2022).

It is believed that a significant obstacle to cancer treatment is chemotherapy resistance. Therefore, identifying new mechanisms of chemoresistance may improve clinical outcomes.

In a study of non-small cell lung cancer (NSCLC), high expression of miR-4443 was found to negatively regulate the m⁶A modification of FSP1 induced by methyltransferase METTL3 to inhibit cisplatin-induced ferroptosis, thereby conferring cisplatin resistance in NSCLC. Therefore, researchers have proposed a novel anticancer strategy to restore METTL3/FSP1-mediated ferroptosis in tumor cells (Song et al., 2021). Some investigators also found that DDX3 reduces tumor stem cell populations by inhibiting the expression of FOXM1 and NANOG. The m⁶A demethylase ALKBH5 was also directly regulated by DDX3, leading to reduced m⁶A methylation in FOXM1 and NANOG nascent transcripts, resulting in chemoresistance. In a patient-derived cell xenograft model of chemo-resistant OSCC, ketorolac restores cisplatin-mediated ferroptosis and significantly reduces tumor burden (Shriwas et al., 2020). PRMT3 inhibitor-mediated METTL14 overexpression promotes methylation through m⁶A-YTHDF2-dependent mechanism, reduces the stability of low GPX4 mRNA, increases lipid peroxidation levels, and accelerates ferroptosis. Thus, blocking PRMT3 may improve the progression of endometrial cancer after cisplatin and radiotherapy (Wang et al., 2023). Moreover, m⁶A hypermethylation resulting from METTL14 modification and YTHDC2 modulation led to the upregulation of FGFR4, which inhibited ferroptosis and conferred anti-HER2 resistance to breast cancer. Further inhibition of FGFR4 in drug-resistant cells revealed that the expression of SLC7A11 and GPX4 was significantly reduced, which promoted ferroptosis to inhibit tumorigenesis, thus restoring the sensitivity of drug-resistant breast cancer cells to anti-HER2 (Zou et al., 2022). In addition, Yang H et al. found that CBSLR, a long-stranded non-coding RNA activated by HIF-1α reverse transcription, is upregulated in gastric cancer and that inhibition of CBSLR under hypoxic conditions leads to chemoresistance. It was shown that lncRNA-CBSLR recruits YTHDF2 protein and CBS mRNA to form a CBSLR/YTHDF2/CBS complex, reducing the stability of CBS mRNA in an m⁶A-dependent manner. It protects GC from ferroptosis in the hypoxic tumor microenvironment, thus revealing a potential therapeutic target for refractory hypoxic tumors (Yang et al., 2022). Fan et al. found that METTL14 targets m⁶A methylation under normoxic conditions at the 5′UTR of SLC7A11 mRNA. m⁶A-modified SLC7A11 mRNA is recognized by YTHDF2 and then sent to the P-body for degradation. Depleting SLC7A11 leads to reduced input of cystine, cysteine and GSH accumulation, which ultimately stimulates ROS production and induces ferroptosis. In contrast, interventional embolization-induced hypoxia inhibits METTL14 in a HIF-1α-dependent manner and subsequently blocks METTL14/YTHDF2/SLC7A11/ROS axis-mediated ferroptosis, promoting HCC progression. This also suggests that targeting the HIF-1α/METTL14/YTHDF2 signaling axis may synergistically affect HCC interventions (Fan et al., 2021).

Of course, in treating malignant tumor diseases, the ultimate goal of studying the mechanisms involved in inhibiting ferroptosis by m⁶A is still to induce its occurrence to inhibit the development of tumor cells. And in the process of traumatic repair, there is also the action of chemotherapeutic drugs causing the malignant growth of normal tissues, which requires the inhibition of ferroptosis. miR-7-5p could effectively inhibit the expression of METLL14 and TFRC and selectively inhibit METTL14/KCNQ1OT1/miR-7-5p positive feedback loop-mediated ferroptosis, which could be used for the treatment of doxorubicin (DOX)-induced cardiac injury, and the approach was able to inhibit the activation of death without necessarily impairing its anticancer activity (Zhuang et al., 2021). METTL14 downregulates the expression of TRAF6 and inactivates the cGAS-STING pathway, thereby alleviating mitochondrial dysfunction and ferroptosis in dopaminergic neurons (Shao et al., 2023). The cardioprotective effect of silencing YTHDF2 is achieved by increasing the stability and expression of SLC7A11, reducing ferroptosis, and providing a new potential therapeutic target for the treatment of ischemic heart disease (Pang et al., 2023).

Taken together, these findings suggest that ferroptosis due to m⁶A modification is essential for regulating cellular homeostasis. m⁶A modification leading to ferroptosis promotes or inhibits malignant cells depending mainly on the level of m⁶A (dynamically regulated by writers and erasers), the function of downstream targets, and changes in target RNA after methylation (depending on the readers), which in turn affects lipid peroxidation or antioxidant enzymes. These findings support the identification of m⁶A regulators involved in aberrant expression in the ferroptosis pathway and as promising biomarkers to predict the prognosis of different cancers.