METTL3, short for methyltransferase-like 3, is the sole catalytic subunit of the methyltransferase complex that catalyzes N6-methyladenosine (m6A), the most abundant mRNA modification. m6A modification is involved in multiple biological processes, regulating gene expression at the post-transcriptional level, which impacts cell functions and disease development [2].

In tumor-infiltrating myeloid cells (TIMs), myeloid deficiency of METTL3 attenuated tumor growth in mice, suggesting its role in promoting tumor immune escape. METTL3 mediated m6A modification on Jak1 mRNA, enhancing JAK1 protein translation and STAT3 phosphorylation [1]. In small cell lung cancer (SCLC), METTL3 is highly expressed in chemoresistant cells and promotes chemoresistance by inducing mitophagy through m6A-mediated degradation of DCP2. Inhibition of METTL3 by STM2457 can reverse SCLC chemoresistance [3]. In breast cancer, knockdown of METTL3 abolished m6A modification on PD-L1 mRNA, reducing its stabilization. Inhibition of METTL3 enhanced anti-tumor immunity through PD-L1-mediated T cell activation [4]. In colorectal cancer, upregulated METTL3 promoted cancer cell proliferation and metastasis by activating the JAK1/STAT3 signaling pathway [5]. In papillary thyroid cancer, downregulation of METTL3 was correlated with poor prognosis, and METTL3 played a tumor-suppressor role through c-Rel and RelA inactivation of the NF-κB pathway and altered neutrophil infiltration [6]. In diabetic nephropathy, podocyte-conditional knockout of METTL3 alleviated podocyte injury and albuminuria in diabetic mice, as METTL3 modulated Notch signaling via m6A modification of TIMP2 [7].

In conclusion, METTL3-mediated m6A modification is crucial in various biological processes and disease conditions. Gene knockout or conditional knockout mouse models have revealed its roles in promoting tumor growth, chemoresistance, and immune escape in cancers, as well as in podocyte injury in diabetic nephropathy. Understanding METTL3-related mechanisms provides potential therapeutic targets for these diseases.