METTL3, also known as methyltransferase-like 3, is the sole catalytic subunit of the methyltransferase complex that catalyzes N6-methyladenosine (m6A) modification, the most abundant mRNA modification. This modification is involved in multiple biological processes, including cell differentiation, development, and disease-related pathways such as immune regulation, cancer progression, and inflammatory responses [2].

In tumor-infiltrating myeloid cells (TIMs), myeloid deficiency of METTL3 attenuated tumor growth in mice. It was found that METTL3 mediated m6A modification on Jak1 mRNA, enhancing JAK1 protein translation and STAT3 phosphorylation, and lactate in the tumor microenvironment induced METTL3 upregulation via H3K18 lactylation [1]. In small cell lung cancer, METTL3 was highly expressed in chemoresistant cells, and its knockdown reversed chemoresistance. METTL3 promoted chemoresistance by inducing mitophagy through m6A-mediated degradation of DCP2 [3]. In breast cancer, METTL3 knockdown reduced m6A modification and stability of PD-L1 mRNA, and inhibition of METTL3 enhanced anti-tumor immunity [4]. In colorectal cancer, upregulated METTL3 promoted cancer cell proliferation and metastasis through activating the JAK1/STAT3 signaling pathway [5]. In papillary thyroid cancer, downregulation of METTL3 was correlated with poor prognosis, and METTL3 knockout-related studies showed its tumor-suppressor role via c-Rel/IL-8-mediated neutrophil infiltration [6]. In diabetic nephropathy, podocyte-conditional knockout of METTL3 alleviated podocyte injury and albuminuria, and METTL3 promoted podocyte injury through m6A-modification of TIMP2 [7].

In conclusion, METTL3-mediated m6A modification plays crucial roles in various biological processes and diseases. Studies using KO/CKO mouse models have revealed its functions in cancer, including promoting tumor growth, chemoresistance, and immune escape, as well as in diabetic nephropathy, highlighting its potential as a therapeutic target in these disease areas.