Alkbh5, short for Alkylation repair homolog protein 5, is an RNA N6-methyladenosine (m6A) demethylase. It modulates m6A modification, which is crucial in RNA metabolism, affecting processes like pre-mRNA processing, mRNA decay, and translation. This regulation impacts various cell functions and is involved in numerous biological processes and disease-related pathways [4].

In multiple disease models, Alkbh5 has shown significant impacts. In mice, macrophage-specific knockout of Alkbh5 inhibits Ang II-induced macrophage-to-myofibroblast transition, ameliorating cardiac fibrosis and dysfunction, indicating its role in hypertensive cardiac fibrosis [1]. Astrocyte-specific deletion of Alkbh5 in mice leads to antidepressant-like behaviors, suggesting its contribution to depressive-like behaviors [2]. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the GCGR and mTORC1 signaling pathways, highlighting its role in metabolic diseases [3]. In addition, Alkbh5 knockout in mesenchymal stem cells (MSCs) aggravates spontaneous osteoarthritis in mice, while its overexpression improves the efficacy of MSCs in osteoarthritis, showing its relation to MSC senescence and osteoarthritis [5]. Conditional knockout of Alkbh5 in tubular epithelial cells alleviates I/R-induced acute kidney injury and fibrosis in male mice [6].

Overall, Alkbh5 plays essential roles in diverse biological functions through its regulation of m6A modification. Studies using gene knockout (KO) and conditional knockout (CKO) mouse models have revealed its significance in diseases such as cardiac fibrosis, depression, metabolic diseases, osteoarthritis, and kidney injury. These models provide valuable insights into the mechanisms of these diseases and potential therapeutic targets related to Alkbh5.

References:

1. Zhuang, Tao, Chen, Mei-Hua, Wu, Ruo-Xi, Zuo, Jun-Li, Ruan, Cheng-Chao. 2024. ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice. In Nature communications, 15, 1995. doi:10.1038/s41467-024-46357-x. https://pubmed.ncbi.nlm.nih.gov/38443404/

2. Guo, Fang, Fan, Jun, Liu, Jin-Ming, Gao, Tian-Ming, Cao, Xiong. 2024. Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice. In Nature communications, 15, 4347. doi:10.1038/s41467-024-48730-2. https://pubmed.ncbi.nlm.nih.gov/38773146/

3. Ding, Kaixin, Zhang, Zhipeng, Han, Zhengbin, Chen, Xiao-Wei, Chen, Zheng. 2025. Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling. In Science (New York, N.Y.), 387, eadp4120. doi:10.1126/science.adp4120. https://pubmed.ncbi.nlm.nih.gov/40014709/

4. Qu, Jianwei, Yan, Haimeng, Hou, Yifan, He, Jingsong, Cai, Zhen. 2022. RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential. In Journal of hematology & oncology, 15, 8. doi:10.1186/s13045-022-01224-4. https://pubmed.ncbi.nlm.nih.gov/35063010/

5. Ye, Guiwen, Li, Jinteng, Yu, Wenhui, Wu, Yanfeng, Shen, Huiyong. 2023. ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. In Experimental & molecular medicine, 55, 1743-1756. doi:10.1038/s12276-023-01059-0. https://pubmed.ncbi.nlm.nih.gov/37524872/

6. Chen, Juntao, Xu, Cuidi, Yang, Kun, Wang, Jina, Zhu, Tongyu. 2023. Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment. In Nature communications, 14, 1161. doi:10.1038/s41467-023-36747-y. https://pubmed.ncbi.nlm.nih.gov/36859428/