Song et al. (61) revealed a significant association between hypothyroidism and the distribution of METTL3 polymorphisms at locus rs3752411 in patients with Hashimoto’s thyroiditis. These findings provide evidence for the correlation between METTL3 mutations and predisposition to AITD and suggest the potential of METTL3 as a therapeutic target for AITD treatment. Another study revealed that both METTL3 and suppressor of cytokine signaling (SOCS) are abnormally expressed in thyroid tissues and CD4+ T cells in Graves’ disease (62). METTL3 knockdown results in the upregulation of SOCS family members (SOCS1, SOCS2, SOCS4, SOCS5, and SOCS6) (62). This study also provides further evidence for the correlation between METTL3-mediated m⁶A modification and AITD ( Table 3 ).

SLE is a chronic autoimmune disease, which might be triggered by the dysfunction of immune cells such as T cells, B cells, monocytes, neutrophils, and dendritic cells (73). The current perspective from the m⁶A modification for the pathogenesis and treatment failure of SLE has enhanced the mechanism understanding of SLE. For example, Luo et al. (74) demonstrated that the METTL3 mRNA levels in peripheral blood from patients with SLE are significantly decreased, which suggests a correlation between METTL3 and patients with SLE. Additionally, excessive activation of CD4+T lymphocytes and imbalanced effector T-cell differentiation contribute to SLE pathophysiology (74). Lu et al. (63) found that METTL3 is at a low level in CD4+ T cells of patients with SLE, which promotes the activation of CD4+ T cells and influences the differentiation of effector T cells, predominantly Treg cells. Moreover, METTL3 deficiency promotes antibody production and aggravates the lupus-like phenotype in mice. METTL3 enhances Foxp3 mRNA decay and reduces Foxp3 expression in an m⁶A-dependent manner, thereby inhibiting Treg cell differentiation. In summary, METTL3 triggers SLE pathogenesis by over-activating CD4+ T cells and dysregulating effector T-cell differentiation via stabilizing Foxp3 mRNA, which could serve as a potential target for therapeutic intervention in SLE. However, Liu et al. (75) reported that METTL3 expressions are elevated in patients with SLE. The upregulated METTL3 promotes IRF4 expression in an m⁶A-dependent manner, thus causing plasma cell infiltration-mediated kidney damage of SLE ( Table 3 ).

RA is a systematic autoimmune disease characterized by chronic synovitis and joint destruction (76). Abnormal proliferation of synovial fibroblast (SF), also termed fibroblast-like synoviocyte (FLS), in the joints and the formation of granulations that erode and destroy the articular cartilage contributes to RA occurrence (77). The typical pathology of RA is the persistence of inflammation maintained by SF and is driven by multiple epi-modifications (78). In addition, fibroblasts can switch from early immunosuppressive to stimulatory in response to relevant factors to promote RA development (79).

SF are effector cells of synovial hyperplasia of RA and are regarded as tumor-like cells with characteristics such as abnormal proliferation, migration and invasion, resistance to apoptosis, and so on (80). SF plays an important role in the development and progression of RA. While promoting apoptosis or inhibiting proliferation, migration, and invasion of SF efficiently prevents RA occurrence and development. Single-cell analysis and machine learning found that the expression levels and enrichment pathways of METTL3 and insulin-like growth factor binding protein 2 (IGFBP2) are different among SF subgroups (64). Further investigation of receptor-ligand interactions found that NPR3 and GHR may have a role in SF interactions (64). As predicted by machine learning, IGFBP2, and METTL3 are identified as key factors regulating m⁶A on NPR3 and GHR (64). In summary, NPR3 and GHR, as well as IGFBP2 and METTL3 perform important regulatory functions in RA. This study provides a basis for future studies to identify pathogenic cell subpopulations and molecular mechanisms in RA. As a chronic inflammatory disorder, FA shows synovial hypertrophy, severe joint damage, and loss of joint function (76). The hyper-proliferating FLS releases a large number of pro-inflammatory indicators, such as IL-6, IL-1b, and TNF-a, causing abnormal inflammation in the synovial membrane (81). Moreover, the activated FLS release matrix metalloproteinases (MMPs), promote FLS migration and invasion (82). Shi et al. (65) and Su et al. (83) found that METTL3 expression is significantly upregulated in human RA synovial tissues and RA rat models. Inhibition of METTL3 suppresses IL-6, MMP-3, and MMP-9 levels in human RA-FLS and rat RA model-FLS (65). In contrast, METTL3 overexpression reverses these effects. Additionally, in FLS, METTL3 regulates the inflammatory response of FLS by activating the NF-kB signaling pathway (65). These findings collectively suggest that METTL3 triggers FLS activation and inflammatory response by targeting the NF-kB signaling pathway. Similarly, METTL3-mediated methylation of RAC2 contributes to cell motility, oxidative stress, and inflammation in TNF-α-stimulated RA fibroblast-like synovial cells (84). Therefore, targeting METTL3 in FLS is a promising therapeutic strategy for RA. As reported, a high level of TTC4 is associated with poor outcomes in patients with RA, which promotes the production of inflammatory factors and reduces the generation of anti-oxidant factors in the articular tissue of mice with RA (66). Lu et al. (66) demonstrated that inhibition of METTL3 reduces TTC4 mRNA stability and expression in articular tissue of mice with RA, which reduces inflammation and oxidative stress by promoting HSP70 expression that further targets NLRP3. In summary, targeted regulation of METTL3 reduces oxidative response and inflammation in the RA model by regulating the TTC4/HSP70/NLRP3 pathway. Therefore, targeting METTL3 is therapeutic for RA ( Table 3 ).

Furthermore, seeking new drugs that suppress the pathological functions of RA-FLS has become a possible method for RA therapy. Artemisinin (ATT) is a well-known antimalarial drug extracted from the plant Artemisia annua L. with immunomodulatory effects, anti-viral effects, anticancer activities, and so on (85). The ATT derivatives of the natural compound ATT show broad anticancer activities without toxicity on normal tissues (86, 87). Recently, ATT has been reported to have the potential to treat RA. Chen et al. (67) reported that ATT administration restrains RA-FLS migration and invasion via suppressing epithelial-to-mesenchymal transition (EMT), as well as inhibiting RA-FLS proliferation and inducing RA-FLS apoptosis. Moreover, ATT treatment relieves RA in mice. RNA-sequencing analysis and bioinformatics analysis identify intercellular adhesion molecule 2 (ICAM2) as a promoter of RA progression in RA-FLS (67). ATT inhibits RA progression by suppressing ICAM2/PI3K/AKT/p300 pathway in RA-FLS. Moreover, ATT inhibits METTL3-mediated m⁶A methylation on ICAM2 mRNA in RA-FLS (67). Interestingly, p300 directly facilitates METTL3 transcription, which could be restrained by ATT in RA-FLS. Importantly, the expression of METTL3, ICAM2, and p300 in synovium tissues of patients with RA is related to clinical characteristics and therapy response (67). This study provides strong evidence that ATT has therapeutic potential for RA management by suppressing proliferation, migration, and invasion, in addition to inducing RA-FLS apoptosis through modulating the feedback loop of METTL3/ICAM2/PI3K/AKT/p300, supplying the fundamental basis for the clinical application of ATT in RA therapy. Moreover, METTL3, ICAM2, and p300 might serve as biomarkers for the therapy response of patients with RA ( Table 3 ).

Primary pSS is a chronic autoimmune disorder defined by xerostomia and keratoconjunctivitis sicca, genetic and epigenetic factors have been considered to affect pSS development (56). Glandular inflammation and tissue impairment eventually give rise to disturbances of secretory and clinical manifestations of dryness, including dry eye and xerostomia (88). pSS is a chronic inflammatory autoimmune disease and is characterized by exocrine gland impairment, such as the salivary and lacrimal glands, which could result in dry mouth and eye (89). Dysregulation of m⁶A modification is closely associated with pSS.

Peripheral blood mononuclear cells (PBMCs) are the effector cells of autoimmune disorders (90). Ma et al. (68) found that the expression level of m⁶A is markedly increased in the PBMCs of patients with pSS and dry eye. The relative mRNA and protein levels of METTL3 and YTHDF1 are markedly elevated in pSS patients with dry eye. The m⁶A RNA level is found to be positively related to METTL3 expression in patients with pSS. The m⁶A RNA level is associated with C4, while METTL3 mRNA expression is associated with C3. This work reveals that the upregulation of m⁶A and METTL3 is associated with the performance of serological indicators and dry eye signs in patients with pSS. METTL3 may contribute to the pathogenesis of pSS-related dry eye ( Table 3 ).

Autoimmune uveitis, a chronic and unpredictable autoimmune disease, is characterized by inflammatory cell infiltration affecting the retina and uvea, which leads to visual disability and even blindness (91). Study has demonstrated that autoreactive Th17 cells are the main drivers of autoimmune uveitis (92). Th17 cells can be categorized into two functionally distinct subsets: non-pathogenic and pathogenic Th17 cells (93). Th17 cells, generated in the presence of TGF-beta, IL-6, IL-17, and IL-10, are largely nonpathogenic (94). In contrast, IL-23 alone or together with IL-6 induces highly pathogenic Th17 cells, which express signature genes including IL-17A, IL-17F, IL-23 receptor (IL-23R), IL-1R1, and granulocyte-macrophage colony-stimulating factor (93). METTL3 maintains the homeostasis of Th17 cells. Zhao et al. (69) found that the expression of METTL3 is decreased, along with reduced m⁶A levels, in eyeballs and T cells of experimental autoimmune uveitis. Overexpression of METTL3 ameliorates the development of experimental autoimmune uveitis and suppresses pathogenic Th17 cell responses in vivo and in vitro. Mechanistically, METTL3 promotes the expression of ASH1L via enhancing its stability in an YTHDC2-dependent manner, which further decreases the expression of IL-17 and IL-23R, resulting in reduced pathogenic Th17 responses. Together, these data reveal a pivotal role of METTL3 in regulating pathogenic Th17 responses, which may contribute to human uveitis therapy ( Table 3 ).

Pathogenic Th17 cells are critical drivers of autoimmune uveitis (95). Wei et al. (70) showed that miR-338-3p endows dendritic cells (DCs) with an increased ability to activate IRBP 1-20-specific Th17 cells by promoting the production of IL-6, IL-1beta, and IL-23. In vivo, administration of miR-338-infected DCs promotes pathogenic Th17 responses and exacerbates uveitis development. Dual-specificity phosphatase 16 (Dusp16) is a target of miR-338-3p (70). miR-338-3p represses Dusp16 and thereby strengthening the p38 signaling, resulting in increased production of Th17-polarizing cytokines and subsequent pathogenic Th17 responses (70). In addition, METTL3 mediates miR-338-3p upregulation in activated DCs. Together, these findings identify a vital role for METTL3/miR-338-3p/Dusp16/p38 signaling in DC-driven pathogenic Th17 responses and suggest a potential therapeutic avenue for uveitis and other Th17 cell-related autoimmune disorders ( Table 3 ).

MG is an autoantibodies-mediated autoimmune disease with complications of deregulated levels of immune factors that are associated with anti-inflammation and pro-inflammation (58). Previous study indicates that the aberrant regulation of immune T cells and inflammatory factors are linked to MG occurrence (58). The NLRP3 inflammasome is present primarily in immune and inflammatory cells following activation by inflammatory stimuli (71). These cells include macrophages, monocytes, DCs, and splenic neutrophils. METTL3 has been reported to regulate the normal function of these immune cells, as well as involved in the regulation of NLRP3 inflammasome. Consistently, Li et al. (72) found that the serum expression level of PTX3 in patients with MG is up-regulated compared to the normal group. METTL3-mediated m⁶A modification decreases PTX3 stability to enhance its expression level, which subsequently induces the STAT3/NLRP3 inflammasome and promotes STAT3 synthesis, promoting inflammation and pyroptosis in patients with MG, as well as in MG mouse model. This study suggests that PTX3 promotes inflammation and pyroptosis by regulating the STAT3/NLRP3 inflammasome signaling pathway, which requires the modification of METTL3. Therefore, targeting METTL3 might be therapeutic for PTX3-induced MG ( Table 3 ).

Collectively, these findings suggest that METTL3 is involved in the pathogenesis of autoimmune diseases. Therefore, we propose that METTL3 may be a valuable diagnostic biomarker and a promising therapeutic target for autoimmune diseases. Nonetheless, additional fundamental and clinical studies are warranted to consolidate the evidence supporting their association and clinical potential.

Abnormally upregulated METTL3 promotes oncogene pescadillo homolog 1 (PES1) translation directly, which enhances the proliferation, sensitivity to imatinib (a tyrosine kinase inhibitor), and resistance of CML cells (98). METTL3, acting as an oncoprotein in CML, specifically modifies PES1 transcripts through its cytoplasmic localization ability rather than its catalytic activity (98). This finding suggests that targeting METTL3 may be a promising therapeutic strategy for tyrosine kinase inhibitor-resistant CML. Lai et al. (99) demonstrated that METTL3 functions indirectly as a downstream target of LINC00470 to modify the oncogene PTEN, thereby suppressing CML cell autophagy and resulting in chemo-resistance. Besides, Yao et al. (100) demonstrated that METTL3-mediated m⁶A modification on the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) effectively downregulates NEAT1 expression in CML, thereby promoting the proliferation and inhibiting the apoptosis of CML cells. Interestingly, the upregulation of miR-766-5p expression is observed in CML PBMCs, which potentially abolishes NEAT1 functions in CML cells (100). miR-766-5p exerts its function by inhibiting the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A) in CML PBMCs. These findings suggest that in CML, METTL3 acts as an oncoprotein by directly targeting the NEAT1/miR-766-5p/CDKN1A axis to promote CML progression ( Figure 2 ).

In summary, the overexpressed level of METTL3 is associated with CML by its direct or indirect oncogenic functions, suggesting that METTL3 is a promising biomarker for CML diagnosis or prognosis, as well as a potential therapeutic target for CML treatment.

AML is a hematologic malignancy characterized by dysregulated proliferation and accumulation of leukemic cells in the hematopoietic system (101). Gao et al. (102) reported that the deletion of METTL3 conditionally in murine fetal liver brings about hematopoietic failure and perinatal lethality. Importantly, loss of METTL3 induces the formation of endogenous dsRNAs that are characterized by high m⁶A modification in their native state, which further activates the aberrant innate immune response and results in hematopoietic defects by triggering the Mavs or Rnasel signaling (102). Furthermore, inhibition of Mavs or Rnasel signaling prevents the aberrant immune response and partially rescues the hematopoietic defects observed in METTL3-deficient cells in vitro and in vivo. These results suggest that METTL3-mediated m⁶A modification regulates the innate immune response during mammalian hematopoietic development ( Figure 2 ).

Additionally, the abnormal differentiation of hematopoietic stem/progenitor cells (HSPCs) is a common feature of AML, which relates to the aberrantly low level of METTL3 (103). Loss of METTL3 enhances the p-AKT level, which contributes to the abnormal differentiation of HSPCs. Overall, METTL3 contributes to HSPC-induced AML by regulating p-AKT, providing a rationale for the therapeutic targeting of METTL3 in AML. As reported, Sun et al. (104) found that the downregulated level of METTL3 represents a novel prognostic factor and a promising therapeutic target for patients with ETV6/RUNX1-positive AML. Targeted suppression of METTL3 in the myeloid lineage reportedly confers protection against age-related and diet-induced non-alcoholic fatty liver disease (NAFLD) and obesity in mice and is accompanied by improved inflammatory and metabolic phenotypes (105). Loss of METTL3 leads to a marked elevation in the mRNA level of DNA damage-inducible transcript 4 (DDIT4) and a strong suppression of mTOR and NF-κB pathway in macrophages in response to cellular stress and cytokine stimulation (105). This indicates that METTL3-mediated m⁶A modification on DDIT4 mRNA results in macrophage metabolic reprogramming during NAFLD and obesity. These findings suggest that METTL3 is actively involved in leukemia ( Figure 2 ).

Furthermore, the abnormally overexpressed METTL3 plays a critical role in AML progression, which relates to different development stages of AML. For example, Sang et al. (106) demonstrated that METTL3 expression is significantly upregulated in most patients with AML. Moreover, METTL3 overexpression is associated with shorter survival time in patients with AML because of its ability to promote cell proliferation and cell cycle progression. Conversely, suppression of METTL3 results in the upregulation of CDKN1A/p21 and reduces mouse double minute 2 (MDM2) mRNA stability, thereby activating the tumor protein 53 (p53) signaling pathway to promote cell proliferation while also facilitating apoptosis and differentiation. These findings suggest that elevated levels of METTL3 play an oncogenic role by targeting the CDKN1A/p21/MDM2/p53 signaling pathway in AML. Similarly, Li et al. (107) uncovered that Yin Yang 1 (YY1) is a transcription factor of METTL3 that interacts with the HDAC1/3 promoter region of METTL3 to promote METTL3 expression in a moderate liquid-liquid phase separation manner, which further enhances the proliferation of AML cells. Therefore, METTL3 acts as the oncogene for AML progression by regulating AML cell proliferation, which might be a biomarker for the developed AML diagnosis. Besides, Wu et al. (108) indicated that METTL3-mediated m⁶A modification on PSMA3-AS1 enhances the stability and level of PSMA3-AS1 in patients with FLT3-ITD+ AML, which in turn promotes AML cell autophagy by targeting miR-20a-5p that further downregulates ATG16L1 mRNA expression, ultimately promotes AML progression. Therefore, METTL3 enhances AML progression by promoting AML cell autophagy via the PSMA3-AS1/miR-20a-5p/ATG16L1 axis, which provides new horizons for early screening and targeted therapy of FLT3-ITD+ AML by targeting METTL3. Furthermore, circular RNAs (circRNAs), a class of non-coding RNAs, serve as important epigenetic regulators in AML progression (109). Large-scale sample detection found that circ-0001187 is only significantly downregulated in newly diagnosed patients with AML whereas is increased in patients with hematological complete remission compared with controls (110). Circ-0001187 sponges miR-499a- 5p to enhance the expression of E3 ubiquitin ligase RNF113A, which further mediates METTL3 ubiquitin/proteasome-dependent degradation to reduce METTL3 expression via K48-linked polyubiquitin chains. The inhibited level of METTL3 promotes proliferation and inhibits apoptosis of AML cells in vitro and in vivo. Therefore, METTL3 serves as the oncogenic target in AML, which is regulated by the circ-0001187/miR-499a-5p/RNF113A axis ( Figure 2 ).

In summary, METTL3 contributes to the development of AML, suggesting its potential for AML diagnosis and classification.

Although great advances have been made in AML therapy, treatment failure occurs in many patients with poor outcomes. Therefore, further investigation of the underlying mechanism for AML treatment failure is required, which might be helpful in exploring new methods to improve AML treatment outcomes.

AML is a distinct hematologic malignancy that targets a specific subpopulation of blood-forming stem/progenitor cells (111). Specifically, AML is characterized by the malignant proliferation of immature bone marrow stem cells in the bone marrow and peripheral blood (112). The adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) confers chemoresistance to AML cells (111, 113). METTL3 plays a vital role in the sensitivity of AML cells to Cytarabine through its interaction with immune-infiltrating cells and autophagy (114). Besides, Pan et al. (115) observed a conspicuous reduction in METTL3 expression in BMSCs obtained from patients with AML, which stimulates BMSC adipogenesis and contributes to AML pathogenesis. The reduced level of METTL3 in BMSCs functions by mediating m⁶A modification on AKT1 transcripts to increase its mRNA stability and induce AKT1 protein expression, thereby activating the PI3K/AKT pathway that causes BMSC adipogenesis and chemoresistance in AML cells. These findings suggest that the METTL3-mediated m⁶A modification on AKT1 is responsible for AML chemoresistance induced by BMSC adipogenesis, hinting at the possibility of targeting METTL3 for BMSC adipogenesis regulation and AML chemoresistance removal. The homing/engraftment in bone marrow (BM) is a crucial step for AML cells to acquire chemoresistance by interacting with stromal cell components, which relates to the upregulated expression of METTL3 in chemoresistant cells (116). Specifically, METTL3-mediated m⁶A modification on ITGA4 mRNA induces ITGA4 expression, which further enhances the homing/engraftment of AML cell chemoresistance in vitro and in vivo. Importantly, inhibition of METTL3 improves homing/engraftment chemoresistance in AML cells. These results suggest that METTL3-mediated m⁶A modification functions in the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors ( Figure 2 ).

Adriamycin chemoresistance poses a great threat in AML therapy (117). Transcriptome-wide analysis of RNA m⁶A modification in Adriamycin-resistant AML cells found that the expression level of METTL3 is elevated, which modifies m⁶A on genes that are enriched in pathways of the FoxO signaling pathway, p53 signaling pathway, and Notch signaling pathway (118). After a combined treatment of STM2457 (an inhibitor of METTL3) and Adriamycin, the proliferation of AML cells is inhibited. Thus, the abnormality of METTL3-mediated m⁶A modification plays an important role in AML Adriamycin resistance. Similarly, low levels of lncRNA maternally expressed gene 3 (MEG3) and miR-493-5p are associated with Adriamycin resistance and poor prognosis in patients with AML (119). Wang et al. (119) found that MEG3 leads to elevated expression of miR-493-5p that further targets METTL3. Subsequently, METTL3 elevates the m⁶A level of MYC to increase MYC expression, leading to Adriamycin resistance in AML cells. Importantly, suppression of METTL3 inhibits AML cell proliferation and promotes their apoptosis, improving Adriamycin sensitivity in AML cells. Collectively, MEG3 and miR-493-5p promote the Adriamycin resistance of AML cells by inactivating the METTL3/MYC axis ( Figure 2 ).

In summary, METTL3 plays an oncogenic role in AML chemoresistance and is associated with poor outcomes in patients with AML. Therefore, we propose that targeting METTL3 represents a rational and promising therapeutic strategy for improving AML treatment failure.