METTL3, short for 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 regulating RNA stability, translation efficiency, and thus impacts various biological processes like cell differentiation, development, and disease-related pathways [2].

In multiple disease models, METTL3 shows distinct effects. In colon cancer, myeloid-specific deletion of METTL3 attenuated tumor growth in mice, suggesting its role in promoting tumor-infiltrating myeloid cell-mediated immunosuppression [1]. In small cell lung cancer, high METTL3 expression was associated with chemoresistance, and its knockdown reversed this phenotype, indicating its function in promoting mitophagy-mediated chemotherapy resistance [3]. In sepsis-associated lung injury, inhibition of METTL3 via knockdown or targeted inhibition suppressed lactate-induced ferroptosis in alveolar epithelial cells and mitigated lung injury in septic mice [4]. In breast cancer, METTL3 knockdown reduced PD-L1 mRNA stability, enhancing anti-tumor immunity [5]. In papillary thyroid cancer, down-regulation of METTL3 was related to malignant progression, and restoring its expression restrained tumor growth [6]. In diabetic nephropathy, podocyte-conditional knockout of METTL3 alleviated podocyte injury and albuminuria [7]. In intrahepatic cholangiocarcinoma, METTL3 knockdown inhibited tumor progression [8].

In conclusion, METTL3-mediated m6A modification significantly influences multiple disease-related biological processes. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models have been crucial in revealing METTL3's role in diseases such as cancer, sepsis-associated lung injury, and diabetic nephropathy. These models help us understand the complex functions of METTL3, providing potential therapeutic targets for these diseases.

References:

1. Xiong, Jia, He, Jia, Zhu, Jun, Lai, Lihua, Wang, Qingqing. 2022. Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. In Molecular cell, 82, 1660-1677.e10. doi:10.1016/j.molcel.2022.02.033. https://pubmed.ncbi.nlm.nih.gov/35320754/

2. Zeng, Chengwu, Huang, Wanxu, Li, Yangqiu, Weng, Hengyou. 2020. Roles of METTL3 in cancer: mechanisms and therapeutic targeting. In Journal of hematology & oncology, 13, 117. doi:10.1186/s13045-020-00951-w. https://pubmed.ncbi.nlm.nih.gov/32854717/

3. Sun, Yueqin, Shen, Weitao, Hu, Shulu, Zhu, Weiliang, Zhang, Jian. 2023. METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy. In Journal of experimental & clinical cancer research : CR, 42, 65. doi:10.1186/s13046-023-02638-9. https://pubmed.ncbi.nlm.nih.gov/36932427/

4. Wu, Dan, Spencer, Charles B, Ortoga, Lilibeth, Zhang, Hao, Miao, Changhong. 2024. Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury. In Redox biology, 74, 103194. doi:10.1016/j.redox.2024.103194. https://pubmed.ncbi.nlm.nih.gov/38852200/

5. Wan, Weijun, Ao, Xiang, Chen, Quan, Luo, Donglin, Xu, Xiang. 2022. METTL3/IGF2BP3 axis inhibits tumor immune surveillance by upregulating N6-methyladenosine modification of PD-L1 mRNA in breast cancer. In Molecular cancer, 21, 60. doi:10.1186/s12943-021-01447-y. https://pubmed.ncbi.nlm.nih.gov/35197058/

6. He, Jing, Zhou, Mingxia, Yin, Jie, Yin, Huiqing, He, Fucheng. 2021. METTL3 restrains papillary thyroid cancer progression via m6A/c-Rel/IL-8-mediated neutrophil infiltration. In Molecular therapy : the journal of the American Society of Gene Therapy, 29, 1821-1837. doi:10.1016/j.ymthe.2021.01.019. https://pubmed.ncbi.nlm.nih.gov/33484966/

7. Jiang, Ling, Liu, Xueqi, Hu, Xueru, Meng, Xiaoming, Wu, Yonggui. 2022. METTL3-mediated m6A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy. In Molecular therapy : the journal of the American Society of Gene Therapy, 30, 1721-1740. doi:10.1016/j.ymthe.2022.01.002. https://pubmed.ncbi.nlm.nih.gov/34995800/

8. Xu, Qiong-Cong, Tien, Yi-Chih, Shi, Yin-Hao, Zhao, Wei, Yin, Xiao-Yu. 2022. METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner. In Oncogene, 41, 1622-1633. doi:10.1038/s41388-022-02185-1. https://pubmed.ncbi.nlm.nih.gov/35094011/