As one of the prevalent posttranscriptional modifications of RNA, N⁷-methylguanosine (m⁷G) plays essential roles in RNA processing, metabolism, and function, mainly regulated by the methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) complex. Emerging evidence suggests that the METTL1/WDR4 complex promoted or inhibited the processes of many tumors, including head and neck, lung, liver, colon, bladder cancer, and teratoma, dependent on close m⁷G methylation modification of tRNA or microRNA (miRNA). Therefore, METTL1 and m⁷G modification can be used as biomarkers or potential intervention targets, providing new possibilities for early diagnosis and treatment of tumors. This review will mainly focus on the mechanisms of METTL1/WDR4 via m⁷G in tumorigenesis and the corresponding detection methods.

Non-alcoholic fatty liver disease (NAFLD) has become a major chronic disease in contemporary society, affected by N6-methyladenosine (m6A) RNA methylation, one of the most common RNA modifications. Compared with healthy control, m6A RNA methyltransferase 3 (METTL3) and METTL14 increased, while Wilms tumor 1-associated protein (WTAP) and RNA-binding motif protein 15 (RBM15) decreased significantly in NAFLD, and the m6A demethylases fat mass and obesity-associated protein (FTO) elevated. Meanwhile, the m6A binding proteins, YT521-B homology (YTH) domain-containing 1 (YTHDC1), YTHDC2, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), and HNRNPA2B1 were decreased, while eukaryotic translation initiation factor 3 subunit H (EIF3H) was increased significantly. All these changes of m6A regulators had significant differences between healthy control and NAFLD, but no differences between the NAFL and NASH group. The expression level of RBM15, HNRNPC, and HNRNPA2B1 were related to body fat index. RBM15, YTHDC2, HNRNPC, HNRNPA2B1, and EIF3H were related to steatosis. Also, KIAA1429 and YTH domain family 1 (YTHDF1) were related to lobular inflammation. Taken together, m6A regulators were involved in the occurrence of NAFLD. More importantly, abnormal MYC was determined as a key link to m6A regulation of NAFLD. The higher MYC mRNA level was accompanied by higher HDL cholesterol and unsaturated fatty acid proportions, as well as lower fat mass, glucose, and transaminase. Taken together, dysregulation of m6A methylation caused steatosis and fibrosis, affecting the occurrence of NAFLD, and MYC might be its potential target.

Multiple animals and in vitro studies have demonstrated that perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure causes liver damage associated with fat metabolism. However, it is lack of population evidence for the correlation between PFAS exposure and nonalcoholic fatty liver disease (NAFLD). A cross-sectional analysis was performed of 1150 participants aged over 20 from the US. Liver ultrasound transient elastography was to identify the participants with NAFLD and multiple biomarkers were the indicators for hepatic steatosis and hepatic fibrosis. Logistics regression and restricted cubic splines models were used to estimate the association between PFASs and NAFLD. PFASs had not a significant association with NAFLD after adjustment. The hepatic steatosis indicators including fatty liver index, NAFLD liver fat score, and Framingham steatosis index were almost not significantly correlated with PFASs exposure respectively. But fibrosis indicators including fibrosis-4 index (FIB-4), NAFLD fibrosis score, and Hepamet fibrosis score were positively correlated with each type of PFASs exposure. After adjustment by gender, age, race, education, and poverty income rate, there was also a significant correlation between PFOS and FIB-4 with 0.07 (0.01, 0.13). The mixed PFASs were associated with FIB-4, with PFOS contributing the most (PIP = 1.000) by the Bayesian kernel machine regression model. The results suggested PFASs exposure appeared to be more closely associated with hepatic fibrosis than steatosis, and PFOS might be the main cause of PFASs associated with hepatic fibrosis.Key messagesCurrent exposure doses of PFAS did not significantly change the risk of developing NAFLD.PFASs exposure appeared to be more closely associated with hepatic fibrosis than steatosis.PFOS might be the main cause of PFASs associated with hepatic fibrosis.

N6-methyladenosine (m6A) methylation is one of the most common RNA modifications, regulating RNA fate at the posttranscriptional level, and is closely related to cellular senescence. Both models of replicative and premature senescence induced by hydrogen peroxide (H₂O₂) were used to detect m6A regulation during the senescence of human embryonic lung fibroblasts (HEFs). The ROS level accumulated gradually with senescence, leading to normal replicative senescence. H₂O₂-treated cells had dramatically increased ROS level, inducing the onset of acute premature senescence. Compared with replicative senescence, ROS changed the expression profiles for m6A-related enzymes and binding proteins, including higher levels of METTL3, METTL14, WTAP, KIAA1429, and FTO, and lower levels of METTL16, ALKBH5, YTHDC1, and YTHDF1/2/3 in the premature senescence persistence group, respectively. Meanwhile, senescent cells decreased total m6A content and RNA methylation enzymes activity, regardless of replicative or premature senescence. Moreover, specific m6A methylation levels regulated the expression of SIRT3, IRS2, and E2F3 between replicative and premature senescence separately. Taken together, differential m6A epitranscription microenvironment and the targeted genes can be used as epigenetic biomarkers to cell senescence and the related diseases, offering new clues for the prevention and intervention of cellular senescence.