Deciphering the secret codes in N⁷-methylguanosine modification: Context-dependent function of methyltransferase-like 1 in human diseases

Oesophageal squamous cell carcinoma

Oesophageal cancer is an aggressive malignancy and the eighth most common cause of cancer death, accounting for more than 70% of all oesophageal cancer cases.⁶⁶ The 5-year survival rate of oesophageal squamous cell carcinoma (ESCC) patients remains very low since it is related to extensive lymphatic spread and vascular invasion; hence, identifying effective therapeutic targets for better treatment of ESCC is highly important.⁶⁷ One study revealed that METTL1 and WDR4 are notably up-regulated in ESCC tissues and are associated with poor prognosis. Mechanistically, abnormal activation of the mTOR pathway results in the phosphorylation and activation of ULK1, mediating the negative regulation of autophagy and initiating the malignant proliferation of ESCC cells. By using tRNA reduction and cleavage sequencing (TRAC-seq) and polyribosome-seq, Han et al.⁶⁸ revealed that METTL1 knockdown leads to decreased expression of m⁷G-modified tRNAs and reduces translation of a subset of oncogenic transcripts enriched in regulatory associated protein of mTOR complex 1 (RPTOR)/ULK1/autophagy signalling. According to these studies, METTL1 and its downstream signalling axis could be the promising therapeutic targets for ESCC treatment.

Hepatocellular carcinoma

HCC accounts for the majority of primary liver malignancies (80–90%) and is the fifth most common cause of cancer-related death.⁶⁶ A recent study revealed that the levels of METTL1 and WDR4 are elevated in HCC and are associated with advanced tumour stages and poor patient survival. METTL1 knockdown decreases the mRNA translation of EGF/EGFR and VEGFA/VEGFR1, reduces the activities of the corresponding downstream signalling pathways, as well as those of AKT and MAPK, and therefore inhibits proliferation and metastasis in HCC.³⁵ Additionally, METTL1 enhances the growth and migration of HCC cells via the suppression of PTEN signalling, suggesting that METTL1 is a promising target for HCC treatment.⁴⁰

Radiotherapy is an increasingly essential therapeutic strategy that plays pivotal roles in the management of HCC; however, resistance to radiotherapy is a primary obstacle to successful treatment outcomes.⁶⁹ Previous investigations have demonstrated that elevated METTL1 expression in tumour tissues is strongly associated with poor prognostic outcomes in HCC patients undergoing radiotherapy. METTL1-mediated m⁷G tRNA modification selectively regulates the translation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) or DNA ligase IV with increased frequencies of m⁷G -related codons after IR treatment, thereby resulting in increased nonhomologous end-joining (NHEJ)-mediated DNA DSB repair efficiency and rendering HCC cells resistant to IR.⁷⁰ Furthermore, disrupting METTL1/TGF-β/PMN-MDSC axis significantly mitigates tumour progression by decreasing PMN-MDSC accumulation and restoring the CD8⁺ T-cell population after RFA.⁶⁰ Thus, METTL1 might be a reliable biotarget to increase the efficacy of radiotherapy in HCC and prevent HCC recurrence after RFA treatment.

The tyrosine kinase inhibitor (TKI) lenvatinib is a first-line treatment for advanced HCC, but resistance still frequently occurs in a considerable proportion of patients.⁷¹ One study revealed that METTL1 and WDR4 are dramatically up-regulated in lenvatinib-resistant cells. Following lenvatinib treatment, METTL1 knockdown overrides resistance by impairing the proliferation capacity and promoting the apoptosis of HCC cells. In addition, METTL1 overexpression induces lenvatinib resistance by increasing the translation of EGFR pathway genes.⁵⁵ These findings indicate that up-regulation of METTL1 strengthens lenvatinib resistance in HCC and confers sensitivity to METTL1 targeting, providing a promising strategy to overcome resistance. These studies have revealed new insights into the role of METTL1 in HCC and provide a molecular basis for HCC diagnosis and treatment.

Intrahepatic cholangiocarcinoma

ICC is a severe malignant tumour that currently comprises 10–20% of primary hepatic tumours.⁷² One study revealed that METTL1 and WDR4 are strikingly increased in ICC and are associated with poor prognosis. This study further revealed the critical role of METTL1-mediated m⁷G tRNA modification in accelerating ICC cell survival and progression by selectively regulating the translation of oncogenic transcripts, including the cell-cycle-related mRNAs cyclin A2 (CCNA2), cyclin D2 (CCND2), CDK6 and CDK8, as well as EGFR pathway genes.⁶³ Another study demonstrated that PMN-MDSCs are enriched in advanced ICC cells and strongly correlated with METTL1. The key translational targets of METTL1 are CXCL8 in humans and CXCL5 in mice, which can facilitate its crucial immunomodulator function in promoting PMN-MDSC accumulation in the TIME and ICC progression. In preclinical ICC mouse models, co-blockade of METTL1 and its downstream chemokine pathway enhances anti-PD-1 efficacy.⁵⁹ In conclusion, the mechanisms of METTL1-mediated changes in the TIME of ICC cells provide new insights for the development of efficient ICC immunotherapeutic strategies.

Colon cancer

CC is a common malignant tumour with high morbidity and mortality worldwide, seriously dampening quality of human life.⁷³ A study utilising the CR-CC cells revealed that METTL1 expression was lower in CR-CC cells than in paired cisplatin-sensitive CC cells. In addition, the S100 calcium-binding protein A4 (S100A4)/p53 axis is the downstream target of METTL1 and miR-149-3p, and overexpressing either METTL1 or miR-149-3p increases p53 protein levels and amplifies the cytotoxic effects of cisplatin in CR-CC cells, which can be reversed by up-regulating S100A4. In general, overexpression of METTL1 sensitises CR-CC cells to cisplatin by modulating the miR-149-3p/S100A4/p53 axis.⁶⁴ These studies provide new gene targets for CC treatment. Additionally, another study revealed that the expression of METTL is markedly up-regulated in colorectal cancer tissues compared with normal tissues and is positively correlated with poor prognosis. METTL1 knockdown suppresses CC cell growth and the G1/S phase transition. Further functional experiments indicated that METTL1 may directly interact with the cell cycle-related gene CHEK2 and suppress its protein expression, thereby attenuating CHEK2-induced G1/S phase arrest.³⁴ Taken together, these results indicate that METTL1 has the ability to modulate CC cell proliferation and progression in a CHEK2-dependent manner, suggesting that METTL1 is a potential therapeutic target for CC.

Gastric cancer

Gastric cancer (GC) is one of the most common malignant tumours of the human digestive tract and it is usually diagnosed at an advanced stage once it is detected due to ambiguous or nonspecific symptoms.⁷⁴ The overall survival rate of patients with GC is still a cause of concern, and detecting genes that are closely related to GC development and have diagnostic and therapeutic implications is particularly important.⁷⁵ One study revealed that the expression level of METTL1 is greater in GC tissues than in normal tissues. The regulatory ability of METTL1 to promote the proliferation and migration of GC cells while inhibiting cell apoptosis may be mediated by tetraspanin 31 (TSPAN31).⁷⁶ Moreover, this may be related to the fact that METTL1 is a flanking gene of the oncogene CDK4, which is enriched on chromosome 12q14–q15.⁷⁷ Although the mechanism by which METTL1 regulates GC cells has not been thoroughly investigated and should be further explored in future studies, METTL1 could be used as a new target for early detection, diagnosis and treatment of GC.

Lung cancer

LC is one of the most common cancers and a leading cause of cancer-related death worldwide.⁷⁸ Mis-regulated epigenetic modifications such as DNA methylation, and RNA and histone modifications, play important roles in LC progression.⁷⁹ One study revealed that the expression levels of METTL1 and WDR4 are noticeably elevated in human LC samples and are negatively associated with patient prognosis. The results of ribosome profiling with nucleotide resolution sequencing (RNC-seq) confirmed that impaired m⁷G tRNA modification upon METTL1/WDR4 depletion could decrease the translation of mRNAs related to the proliferation, invasion and tumourigenic capacities of LC cells. Furthermore, overexpression of the METTL1 downstream target CCND3 partially rescues the growth and invasion capacities of METTL1-depleted LC cells.⁴³ These findings provide strong evidence that METTL1 promotes LC growth and invasion through the regulation of m⁷G tRNA modifications, selectively promoting the translation of oncogenes and modulating the processes of cell cycle-related mRNAs. However, another study confirmed that METTL1 inhibits the proliferation of LC A549 cells by promoting the processing of pri-let-7e miRNA transcripts into precursor pre-let-7e miRNA and mature let-7e miRNA, which negatively regulates the oncogene high mobility group AT-hook 2 (HMGA2).²⁴ HMGA2 is known to facilitate the epithelial–mesenchymal transition (EMT) and expedite cancer progression, thereby contributing to unfavourable patient outcomes.⁸⁰ METTL1 knockdown increases HMGA2 mRNA expression and protein levels in LC cells, whereas the transfection of mature let-7e miRNA reverts the up-regulation of the HMGA2 protein caused by METTL1 depletion.²⁴ Therefore, the functions of METTL1 in LC are still not fully understood, and further in-depth research is essential for the development of new therapeutic strategies for effective LC treatment.

Bladder cancer

BCa is the fifth most common malignancy and frequently exhibits rapid progression, distant metastasis and a consequently poor prognosis.^{66, 81, 82} Thus, it is imperative to identify potential therapeutic targets for improved BC treatment. A study confirmed that METTL1-mediated m⁷G tRNA modification promoted the proliferation, migration and invasion of BCa cells by increasing the protein expression of EGFR/EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1).⁴⁴ EGFR is a key receptor involved in signalling pathways that drive tumour progression. The PI3K/AKT pathway, which is downstream of EGFR, can be activated by the EGFR–ligand interaction, driving cancer cell proliferation, survival and invasion.⁸³ Furthermore, the binding EGFR results in the autophosphorylation of EGFR and the activation of downstream signalling pathways that accelerate BCa progression. In addition, Xie et al.⁴⁵ reported that METTL1 drives tumour progression in BCa by promoting the processing of miR-760 in a m⁷G-dependent manner through the combination of miRNA-seq and m⁷G methylated RNA immunoprecipitation sequencing (MeRIP-seq). ATF3 is a potential target of miR-760 and can be degraded by miR-760. ATF3 overexpression significantly represses the proliferation and migration of BCa cells by influencing the expression of cell cycle-associated proteins and EMT-associated proteins.⁸⁴ Taken together, these findings reveal a regulatory axis composed of METTL1/miR-760/ATF3 in regulating BCa progression and provide a new avenue for BCa treatment.

Surprisingly, emerging evidence indicates that m⁷G-3′-tiRNA Lys(TTT) (mtiRL), a novel m⁷G-modified tRNA-derived small RNA (tsRNA) catalysed by METTL1, plays an oncogenic role in BCa in vitro and in vivo. Specifically, METTL1, the tRNA m⁷G-modifying enzyme, catalyses the formation of mtiRL, which selectively binds to the oncoprotein annexin A2 (ANXA2). This binding promotes the Tyr24 phosphorylation of ANXA2 by enhancing its interaction with Yes proto-oncogene 1 (Yes1). Consequently, the phosphorylated ANXA2 (p-ANXA2-Y24) is more likely to translocate to the nucleus in BCa cells, thereby augmenting the proliferation and migration of these cells.⁸⁵ In summary, this study reveals a novel mechanism of tsRNA epigenetic regulation in BCa malignancy, and METTL1, a tRNA m⁷G-modifying enzyme, plays a considerable role in BCa treatment.

Prostate cancer

PCa is the second leading cause of cancer-related death in men.⁶⁶ Conventional therapies target the hormonal axis of the disease with more than 30% of patients eventually developing resistance to therapy and metastasis, highlighting the need to identify potential alternative and targetable molecular pathways for PCa treatment.⁸⁶ One study demonstrated that METTL1 is the main epigenetic transcriptome regulatory factor in primary and advanced prostate tumours and that its overexpression is associated with poor prognosis. Specifically, METTL1‑mediated methylation protects tRNAs from cleavage into small noncoding RNAs, while METTL1 depletion causes the loss of m⁷G tRNA methylation and promotes the biogenesis of a novel class of small noncoding RNAs derived from 5′-tRNA fragments.⁶¹ 5′-tRNA-derived small RNAs play critical roles in activating interferon (IFN) signalling pathways, immune effector processes and catabolic processes, thus suppressing PCa cell growth. In addition, in preclinical PCa models, METTL1 knockdown increases the secretion of cytokines involved in proinflammatory activity, which polarises macrophages to the M1-like endotype and induces the down-regulation of anti-inflammatory cytokines which can polarise macrophages to the M2-like endotype, indicating that METTL1 inhibition can polarise immune cells in the tumour microenvironment (TME) toward a cytotoxic tumouricidal endotype and enhance the response to immunotherapy.⁶¹ Furthermore, METTL1 can add m⁷G modifications to CDK14 mRNA, increasing its mRNA stability and ultimately promoting CRPC progression.³⁶ In summary, these findings reveal a therapeutically actionable role of METTL1 in PCa.

Adrenocortical carcinoma

ACC is a highly malignant and aggressive urologic cancer, and patients commonly present with advanced or metastatic disease at the time of initial diagnosis due to atypical incipient symptoms, with a 5-year overall survival rate of less than 15%.^{87, 88} METTL1 overexpression stimulates the proliferation, migration and invasion of ACC cells, whereas METTL1 silencing significantly retards tumour growth in mouse xenograft model.⁴¹ In addition, the levels of infiltrating CD8⁺ T cells is greater and that of macrophages is lower in clinical ACC samples with low METTL1 expression than in those with high METTL1 expression. Collectively, these results indicate that METTL1 plays a pro-oncogenic role in ACC progression and profoundly affects the tumour immunity of ACC.

Acute myeloid leukaemia

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults, and the prognosis of elderly individuals, who account for the majority of new cases, remains poor.⁶⁶ METTL1 is frequently overexpressed in AML and is associated with poor patient survival. METTL1 increases the abundance of m⁷G-modified tRNAs, particularly Arg-TCT-4-1, as well as the translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon, altering the cell cycle and inducing oncogenic transformation.⁸⁹ As a result, this study validates the potential therapeutic role of METTL1-mediated tRNA m⁷G modification in AML cell translation control and tumour biology.

Head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers and develops from the mucosal epithelium in the oral cavity, pharynx and larynx.⁶⁶ There is a clinical need to develop effective therapeutic regimens for HNSCC patients including molecular targeted therapy. A recent study revealed that METTL1/WDR4 accelerates HNSCC progression and metastasis and is associated with a poor prognosis. Up-regulation of METTL1 affects the m⁷G levels of 16 tRNAs, promoting the translation of a subset of oncogenic transcripts, which includes genes related to the PI3K/AKT/mTOR signalling pathway.⁹⁰ Chemical modulators of the PI3K/AKT/mTOR signalling pathway have also been shown to counteract the effects of METTL1 in mouse HNSCC. In addition, single-cell RNA sequencing revealed that METTL1 knockout in mouse tumour cells alters the immune landscape and cell-cell interactions between the tumour and stromal compartments. In conclusion, this work provides novel insights into tRNA modification-mediated regulation of mRNA translation and highlights the critical function of METTL1 in HNSCC progression.

Nasopharyngeal carcinoma

More than 70% of NPC cases occur in East Asia and Southeast Asia, with terminal patients having poor prognoses, and treatment options are very limited for those patients after disease progression.^{91, 92} These findings emphasise the strong need for further investigations to identify potential targets of NPC therapies. Recent research has demonstrated that overexpression of METTL1 promotes NPC growth and metastasis, which is associated with poor prognosis. METTL1-mediated m⁷G tRNA modification activates the WNT/β-catenin signalling pathway in NPC to increase the translation of cyclins and associated oncogenes, including cyclin D1 and c-Myc, thereby promoting the proliferation and migration of cancer cells.⁴⁷ In addition, METTL1 promotes NPC cell EMT and chemoresistance to cisplatin and docetaxel through the WNT/β-catenin signalling pathway. Collectively, these results indicate that METTL1 could serve as both a therapeutic target and a marker for individualised chemotherapy strategies for NPC.

Oral squamous cell carcinoma

OSCC is the most lethal form of HNSCC worldwide, leading to a poor prognosis because of its high recurrence and metastasis rates in advanced stages.⁹³ Most patients eventually acquire resistance to anlotinib, an oral multitarget TKI that is potently antitumourigenic.⁹⁴ METTL1 up-regulation decreases the antiproliferative and proapoptotic effects of anlotinib while enhancing cell migration and has a markedly inverse correlation with tumour growth inhibition rates. Mechanistically, the overexpression of METTL1 in anlotinib-resistant OSCC cells contributes to increased global mRNA translation and drives a metabolic reprogramming shift from glycolysis to OXPHOS through m⁷G tRNA modification, and the inhibition of OXPHOS biochemically negates the effect of METTL1 on anlotinib resistance.⁴⁶ Overall, this study underscores the pivotal role of METTL1 in anlotinib resistance and lays the groundwork for novel therapeutic interventions to counteract resistance in OSCC.

Ameloblastoma

Ameloblastoma (AM) is the most prevalent epithelial odontogenic tumour within the oral and maxillofacial region, accounting for approximately 1% of all oral tumours, and the high recurrence rate of AM is closely related to its invasive growth behaviour.⁹⁵ High METTL1 expression is strongly associated with postoperative recurrence in AM, and knocking down METTL1 inhibits the proliferation, migration and invasion of AM cells both in vitro and in vivo. Research has revealed that down-regulation of METTL1 results in decreased translation levels of downstream genes from the MAPK signalling pathway, such as cyclin D1, matrix metalloproteinase-2 (MMP2), MMP9 and vimentin, further confirming the regulatory role of METTL1 in the invasive growth of AM.⁹⁶ These results suggest that METTL1 promotes the invasive development of AM and that the expression level of METTL1 has potential application value for predicting the prognosis of AM.

Breast cancer

BC is the most frequently diagnosed cancer in women worldwide, and its incidence rate has been increasing steadily.⁹⁷ Recent research suggests that patients with luminal-type BC may benefit from CDK4/6 inhibitor therapy, but predictive targets for guiding treatment selection are lacking.⁹⁸ METTL1 and WDR4 overexpression in BC is correlated with poor patient prognosis, underscoring their importance in BC development. More than 50% of genes co-expressed with METTL1 and WDR4 exhibit up-regulated expression patterns in BC, with functional enrichment in critical cellular processes including cell cycle regulation, DNA replication and nucleocytoplasmic transport mechanisms, all of which contribute to BC progression and metastatic dissemination.⁹⁹ Contrary to these observations, our comprehensive investigation employing m⁷G tRNA MeRIP-seq and ribosome profiling sequencing (Ribo-seq) revealed that METTL1-mediated tRNA m⁷G modification exerts inhibitory effects on BC cell cycle progression and proliferative capacity. Mechanistically, METTL1 increases the m⁷G levels of 19 tRNAs to modulate the translation of GADD45A and RB1, which interact with CDKs and cyclin B1 (CCNB1), thereby leading to G2/M phase cell cycle arrest in BC cells. Furthermore, our data indicated that overexpression of METTL1 enhances abemaciclib, a CDK4/6 inhibitor, which targets the RB1 tumour suppressor protein and causes G1/S phase cell cycle arrest in tumour cells, and the combined treatment of abemaciclib with METTL1 lentivirus (LV-METTL1) is more effective at inhibiting tumour growth than either treatment alone.³⁸ These findings confirmed that METTL1 plays a critical role in BC and provide a promising strategy for improving the therapeutic benefits of CDK4/6 inhibitors in the treatment of BC patients.

Ovarian cancer

Ovarian cancer (OC) is a malignant gynaecological disease of the female reproductive system and is the sixth most common cause of death in women.⁶⁶ Owing to its strong association with poor prognosis in OC, METTL1, as a differentially expressed RNA-modification regulatory gene, was chosen to construct a signature model with LASSO regression analysis, and its risk score was negatively correlated with that of METTL1. Furthermore, the risk score was positively correlated with CD4⁺ memory resting T cells and negatively correlated with M1 macrophages and plasma cells.¹⁰⁰ It is an independent prognostic model for patient stratification, prognostic evaluation and prediction of response to immunotherapy. Although this study emphasised the important roles of METTL1 in OC pathological features and prognosis, no specific experimental evidence has demonstrated the association between METTL1 and OC malignant behaviours. Taken together, these results indicate that further in-depth research is needed to identify the functional role of METTL1 in OC progression.

Teratoma

Deng et al.⁵⁰ reported that METTL1-knockdown hiPSCs tend to differentiate into mesoderm with neovascularisation while inhibiting neuroectoderm differentiation. Increased angiogenesis is often associated with increased cancer cell proliferation and tumour growth.¹⁰¹ In nude mice, METTL1-KD hiPSCs clearly enhance teratoma formation by promoting cell proliferation and angiogenesis by decreasing the mRNA levels of the stem cell transcription factors recombinant octamer binding transcription factor 4 (Oct4), Nanog and sex-determining region Y (Sox2), providing novel insight into the potential role of METTL1 in teratoma treatment.⁵⁰

Glioma

Glioma, which is derived from glial cells, is the most frequently diagnosed malignant tumour of the central nervous system and accounts for more than half of all malignant brain tumours.¹⁰² Glioma is characterised by a high recurrence rate and mortality, and the treatment efficacy of current treatment strategies has not been satisfactory. METTL1 expression continuously increases with increasing glioma grade and was significantly greater in glioma tissues than in adjacent noncancerous tissues. In addition, the results of functional enrichment and pathway analyses indicate that the molecular mechanism by which high METTL1 promotes glioma proliferation is potentially related to the MAPK signalling pathway, and further study of the relationship between METTL1 and this pathway is necessary.¹⁰³ Furthermore, high METTL1 expression is associated with poor prognosis and survival of patients with glioma. METTL1 may be used as a valuable independent risk factor, and further investigations are warranted to explore its clinical application.

Neuroblastoma

Neuroblastoma (NBL) is the most universal malignant tumour in infancy and the most common extracranial solid tumour in childhood, with extremely low survival for advanced NBL.¹⁰⁴ A recent study revealed that METTL1 is noticeably up-regulated in advanced NBL and plays a crucial role in promoting NBL progression, whereas down-regulation of METTL1 inhibits cell proliferation and decreases the migration ability of NBL cells. Furthermore, m⁷G profiling and translation analysis demonstrated that METTL1-mediated tRNA m⁷G modification crucially selectively regulates NBL cell mRNA translation in a m⁷G-related codon-dependent manner. Knockdown of METTL1 reduces the levels of both m⁷G modification and m⁷G tRNA expressions, with impaired translation of 339 overlapping genes enriched in oncogenic pathways in NBL cells, including metadherin (MTDH, also known as AEG-1 and Lyric) and programmed cell death 10 (PDCD10).¹⁰⁵ In summary, this study reveals the tumour-promoting role of METTL1-mediated tRNA m⁷G modification in controlling NBL progression, providing a potential strategy for the clinical management of NBL.

Osteosarcoma

Osteosarcoma is one of the most common primary bone tumours and is associated with a high mortality rate in children and adolescents, and surgery combined with adjuvant chemotherapy is the most effective treatment for osteosarcoma patients.^{106, 107} Owing to its high metastasis and drug resistance rates, the clinical outcomes for osteosarcoma patients have not improved.¹⁰⁸ METTL1 is frequently amplified in osteosarcoma and is associated with poor patient prognosis. METTL1 knockdown decreases the tRNA m⁷G modification level and impairs osteosarcoma progression, whereas METTL1 overexpression promotes osteosarcoma proliferation, migration and invasion. In detail, m⁷G dysregulation of tRNAs mediated by METTL1 increases the translation of genes associated with extracellular matrix remodelling, an important factor contributing to chemoresistance in cancers, including LOXL2, which facilitates osteosarcoma progression and chemoresistance to doxorubicin.⁴² However, another study revealed that METTL1 expression is markedly lower in osteosarcoma tissues than in normal bone tissues and that METTL1 expression decreases with increasing clinical stage. Furthermore, METTL1 promotes primary pri-miR-26a maturation by increasing RNA stability in a manner dependent on m⁷G methylation. The increase in mature miR-26a-5p can further target FTH1 mRNA and eliminate FTH1 translation efficiency, increasing ferroptosis and promoting the sensitivity of osteosarcoma cells to chemotherapeutic drugs.⁵⁴ Thus, more experimental evidence is needed to clarify the specific function of METTL1 in osteosarcoma.

Systemic lupus erythematosus

SLE is caused by pathogenic autoantibodies and has diverse clinical manifestations caused by the phenotypic and functional abnormalities of immune cells.¹⁰⁹ Conventional treatments are often accompanied by unwanted side effects such as kidney damage and infection, which seriously impair the quality of life of SLE patients, and targeted and individualised therapy should be further developed.¹¹⁰ One study suggested that METTL1 is down-regulated in patients with SLE and that METTL1 is positively correlated with the number of peripheral blood B cells but negatively correlated with the number of suppressor T cells, indicating that METTL1 deficiency has the potential to participate in the progression of SLE.⁶⁵ Furthermore, METTL1 expression is negatively correlated with aberrant immune pathways, including the Notch signalling pathway, Fc receptor-mediated phagocytosis, the MAPK pathway and the Toll-like receptor signalling pathway, which are reportedly to be involved in SLE by regulating immune cells or inflammatory cytokines.^{65, 111-114} In addition, METTL1 is positively correlated with activated CD8 T⁺ cells and activated CD4⁺ T cells, which are abnormally activated because of aberrant T-cell signalling pathways, resulting in inflammatory responses, which facilitate B cells and autoimmunity.^{65, 115} These results indicate that METTL1 might influence the immune response by affecting the dysregulation of immune cells in SLE, which might be explored for a more effective immunotherapy for SLE.

Multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease with a complex pathogenesis in which neurodegeneration and demyelination are the main contributors to disability.¹¹⁶ Tag-single nucleotide polymorphism analysis in MS patients revealed that a functional variant (rs10877013) strongly affects the activity of one enhancer in the 12q13.3–12q14.1 region in an allele-dependent and orientation-dependent manner, which could be the cause of the alteration in KIF5A–CYP27B1–METTL1–FAM119B locus gene expression due to the promoter multigene interactions observed in the region.¹¹⁷ In addition, MS patients have lower levels of vitamin D in their serum, which has a suppressive role in the adaptive immune system. CYP27B1, as an enzyme induced by PTH and implicated in vitamin D activation, could be the causal gene.¹¹⁸ It has been proposed that deletion of METTL1 results in loss of PTH activation of CYP27B1, implying a link between METTL1 and the pathogenesis of MS.¹¹⁹

Osteoarthritis (OA)

Osteoarthritis (OA) is the most common form of arthritis and has a poor prognosis, affecting more than 7% of the global population.¹²⁰ Unfortunately, there is a lack of satisfactory treatments for effectively treating OA patients in the clinical.¹²¹ Analysis revealed that METTL1 expression is lower in OA samples than in healthy samples and is strongly correlated with immune cells and immunological function. METTL1 was identified as a novel m⁷G hub biomarker through an intersection analysis during the progression of OA and was used to construct a model to predict the occurrence of OA.¹²² This study highlights the importance of METTL1 in OA, which contributes to enhancing our understanding of immune infiltration characterisation and guides the development of more effective immunotherapy strategies.

Alzheimer's disease

Alzheimer's disease (AD) is the most common irreversible type of dementia characterised by cognitive dysfunction and marked neuronal loss, which is attributed to adult hippocampal neurogenesis impairment.^{123, 124} The expression of METTL1 and the m⁷G modification level in neurons are considerably increased compared with those in neural stem cells, and METTL1 overexpression enhances neuronal differentiation and proliferation. Mechanistically, METTL1-mediated internal m⁷G modification facilitates SPTBN2 expression by increasing SPTBN2 mRNA stability and translation, hence promoting neurogenesis. In addition, METTL1 knockdown reduces hippocampal neurogenesis and spatial memory, whereas METTL1 overexpression rescues defective neurogenesis and cognitive impairment in adult mice.¹²⁵ These results suggest that targeting METTL1-mediated regulation of neurogenesis could be a potential therapeutic option for the treatment of AD.

Cardiac hypertrophy

Cardiac hypertrophy is a compensatory response of the myocardium to mechanistic stress provoked by various cardiac disorders, and pathological cardiac hypertrophy stemming from persistent stress is an independent risk factor for the development of heart failure (HF).¹²⁶ Deficiency of METTL1 attenuates cardiac hypertrophy and dysfunction upon pressure overload from transverse aortic constriction or angiotensin II stimulation, whereas cardiac-specific overexpression of METTL1 drives cardiac remodelling. Mechanistically, METTL1 increases SRSF9 expression by inducing m⁷G modification of SRSF9 mRNA, which enhances alternative splicing and the stability of NFATc4, ultimately leading to a prohypertrophic phenotype and facilitating hypertrophic cardiac growth.⁶² This study reveals that METTL1 plays an important role in driving cardiac hypertrophy by regulating the SRSF9/NFATc4 axis, suggesting that targeting METTL1 could be an efficient way to treat cardiac hypertrophy and HF.

Cardiac injury

Myocardial infarction leads to functional cardiac cell injury, which is the basic pathological process that induces HF.¹²⁷ METTL1 has been shown to increase m⁷G methylation of ATF5 mRNA and increase ATF5 expression, thereby promoting the transcription of INCA1, an inhibitor of CDK2 that interacts with cyclin A1, resulting in S to G2/M cell cycle arrest and suppressing cardiomyocyte proliferation and cardiac regeneration.^{37, 128} Moreover, METTL1 improved the deubiquitinase cylindromatosis (CYLD) mRNA stability by inducing m⁷G modification of CYLD mRNA, thereby leading to increased CYLD protein expression. This process results in an increase in the CYLD-mediated deubiquitination of P53 and ultimately leads promotes cardiomyocyte apoptosis in cardiac ischemia/reperfusion injury.¹²⁹ Hence, these findings reveal that METTL1-mediated m7G methylation is involved in the regulation of cardiomyocyte proliferation, opening new avenues for alleviating cardiac injury and promoting cardiac repair and regeneration.

Cardiac fibrosis

Cardiac fibrosis is a common pathology of heart disease that damages the heart physically and electrically.^{130, 131} Therefore, identifying potential targets for the treatment of cardiac fibrosis is crucial. A recent study demonstrated that METTL1-mediated RNA m⁷G methylation is elevated in cardiac fibrosis tissues and that TGF-β1-induced myofibroblast transformation of cardiac fibroblasts is an important step in the development of cardiac fibrosis. Furthermore, fibroblast-specific knockout of METTL1 decreases the number of m⁷G-methylated fibrotic genes and impairs their translation efficiency, thereby attenuating MI-induced HF and cardiac fibrosis.¹³² Overall, these findings suggested a novel profibrosis role of METTL1-mediated m⁷G methylation and that targeting METTL1 could be a potential and attractive therapeutic strategy for cardiac fibrosis.