Alkbh3, short for Alpha-ketoglutarate-dependent Dioxygenase alkB Homolog 3, is an important m1A RNA demethylase. N1 -methyladenosine (m1A) RNA modification is a key regulator of RNA metabolism, and Alkbh3's demethylation activity impacts RNA processing, structure, and function of targets [5]. It is involved in multiple biological processes, including ciliogenesis, neurogenesis, and is related to various disease conditions such as cancer and fibrosis [2,3,6].

In high-risk ocular melanoma, excessive histone lactylation upregulates Alkbh3, which then promotes tumor progression by demethylating m1A on SP100A, a core component of PML bodies, leading to the attenuation of tumor-suppressive PML condensates [1]. In mammalian cells, Alkbh3 inhibits ciliogenesis by demethylating m1A sites on Aurora A mRNA, and alkbh3 morphants in zebrafish embryos show ciliary defects [2]. In pathological skin fibrosis, Alkbh3 exerts a pro-fibrotic effect by demethylating m1A on METTL3 mRNA, which stabilizes extracellular matrix components [3]. In gastric cancer, PUS7-dependent pseudouridylation of Alkbh3 mRNA enhances its translation, and Alkbh3 functions as a tumor suppressor [4]. In neural stem cells, depletion of Alkbh3 decreases m1A modification, neuronal differentiation and proliferation, while overexpressing Alkbh3 has the opposite effect, and this is mediated by the m1A demethylation of Mmp15 mRNA [6]. Also, Alkbh3 can regulate the glycolysis of cancer cells by demethylating m1A on ATP5D mRNA [7].

In conclusion, Alkbh3 is crucial for various biological processes through its m1A demethylation activity. Its role in diseases such as cancer and fibrosis has been revealed through functional studies, which help in understanding the underlying molecular mechanisms. These findings suggest that Alkbh3 could be a potential target for disease treatment and prevention in related disease areas.

References:

1. Gu, Xiang, Zhuang, Ai, Yu, Jie, Fan, Xianqun, Chai, Peiwei. . Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A. In Nucleic acids research, 52, 2273-2289. doi:10.1093/nar/gkad1193. https://pubmed.ncbi.nlm.nih.gov/38118002/

2. Kuang, Wenjun, Jin, Hao, Yang, Feng, Xie, Shanshan, Zhou, Tianhua. 2022. ALKBH3-dependent m1A demethylation of Aurora A mRNA inhibits ciliogenesis. In Cell discovery, 8, 25. doi:10.1038/s41421-022-00385-3. https://pubmed.ncbi.nlm.nih.gov/35277482/

3. Tu, Liying, Gu, Shuchen, Xu, Ruoqing, Zhao, Yixuan, Zan, Tao. 2025. ALKBH3-Mediated M1A Demethylation of METTL3 Endows Pathological Fibrosis:Interplay Between M1A and M6A RNA Methylation. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), , e2417067. doi:10.1002/advs.202417067. https://pubmed.ncbi.nlm.nih.gov/40019372/

4. Chang, Yongxia, Jin, Hao, Cui, Yun, Xie, Shanshan, Zhou, Tianhua. . PUS7-dependent pseudouridylation of ALKBH3 mRNA inhibits gastric cancer progression. In Clinical and translational medicine, 14, e1811. doi:10.1002/ctm2.1811. https://pubmed.ncbi.nlm.nih.gov/39175405/

5. Li, Jiexin, Zhang, Haisheng, Wang, Hongsheng. 2022. N1-methyladenosine modification in cancer biology: Current status and future perspectives. In Computational and structural biotechnology journal, 20, 6578-6585. doi:10.1016/j.csbj.2022.11.045. https://pubmed.ncbi.nlm.nih.gov/36467585/

6. Wang, Huan, Xie, Linjie, Guo, Haomin, Kong, Xuejian, Xuan, Aiguo. 2024. m1A demethylase Alkbh3 regulates neurogenesis through m1A demethylation of Mmp15 mRNA. In Cell & bioscience, 14, 92. doi:10.1186/s13578-024-01275-9. https://pubmed.ncbi.nlm.nih.gov/39004750/

7. Wu, Yingmin, Chen, Zhuojia, Xie, Guoyou, Niu, Hongxin, Wang, Hongsheng. 2022. RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2119038119. doi:10.1073/pnas.2119038119. https://pubmed.ncbi.nlm.nih.gov/35867754/