Alkbh3, short for Alpha-ketoglutarate-dependent Dioxygenase alkB Homolog 3, is an m1A demethylase. N1-Methyladenosine (m1A) RNA modification is a crucial regulator of RNA metabolism, and Alkbh3 plays a key role in this process by removing m1A methylation. It is involved in multiple biological pathways such as ciliogenesis, neurogenesis, and is also associated with cancer progression and pathological fibrosis [2,3,5]. Genetic models, like gene knockout (KO) mouse models, are valuable for studying its functions.

In melanoma, silencing Alkbh3 shows therapeutic efficacy both in vitro and in vivo, as histone lactylation-boosted Alkbh3 promotes tumor progression by m1A demethylation of SP100A and reducing promyelocytic leukemia protein nuclear condensates [1]. In ciliogenesis, depletion of Alkbh3 in mammalian cells enhances Aurora A mRNA decay and inhibits its translation, leading to ciliary defects in zebrafish embryos, which can be rescued by wild-type alkbh3 [2]. In pathological skin fibrosis, ablation of Alkbh3 inhibits the progression of hypertrophic scars (HTS) in vitro and in vivo, as Alkbh3-mediated m1A demethylation of METTL3 endows pathological fibrosis [3]. In gastric cancer, PUS7-dependent pseudouridylation of Alkbh3 mRNA enhances its translation and suppresses cancer progression, suggesting Alkbh3 may act as a tumor suppressor [4]. In neurogenesis, depletion of Alkbh3 in neural stem cells decreases m1A modification, neuronal differentiation and proliferation, while overexpressing it has the opposite effect, with the m1A demethylation of Mmp15 mRNA by Alkbh3 promoting neurogenesis [5]. In cancer cells, ALKBH3 can regulate glycolysis in a demethylation-activity-dependent manner, and targeted demethylation of ATP5D m1A can increase ATP5D expression and cancer cell glycolysis [6].

In conclusion, Alkbh3 is essential for regulating m1A-mediated RNA metabolism in various biological processes. Studies using KO/CKO mouse models and other loss-of-function experiments have revealed its significance in cancer, ciliogenesis, pathological fibrosis, and neurogenesis, providing insights into potential therapeutic targets for related diseases.