Ddx21, a member of the DEAD-box RNA helicase family, plays a pivotal role in multiple aspects of RNA metabolism, including ribosomal RNA (rRNA) processing, transcription, and translation [8]. It is involved in various biological processes such as tissue differentiation, mRNA splicing, and is associated with pathways like epithelial-mesenchymal transition (EMT) in cancer progression. Its functions are crucial for maintaining genome stability and normal cellular activities. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, could potentially provide in-depth insights into its gene function [8,9].

Glucose binds to the ATP-binding domain of Ddx21, altering its conformation, inhibiting helicase activity, and dissociating Ddx21 dimers, which is essential for epidermal differentiation as it promotes the splicing of pro-differentiation genes [1]. Ddx21 mediates co-transcriptional RNA m6A modification, interacting with METTL3 and promoting transcription termination and genome stability, with disruption leading to defective termination and DNA damage [2]. SLERT lncRNA interacts with Ddx21, altering the Ddx21 ring-shaped structures that suppress pre-rRNA transcription, thus controlling ribosome biogenesis [3]. In colorectal cancer, Ddx21 is highly expressed, and its phase separation promotes metastasis via the MCM5-dependent EMT pathway [4]. Ddx21 coordinates transcription and ribosomal RNA processing, associating with Pol I-and Pol II-transcribed genes and promoting rRNA transcription, processing, and modification, as well as facilitating Pol II transcription elongation [5]. In breast cancer, PARP-1 activation by snoRNAs ADP-ribosylates Ddx21, affecting rDNA transcription and ribosome biogenesis [6]. In acute myeloid leukaemia, super-enhancer-driven IGF2BP2 and IGF2BP3 upregulate Ddx21 in an m6A-dependent manner, promoting leukaemia progression [7].

In conclusion, Ddx21 is essential for RNA metabolism, tissue differentiation, and genome stability. Through model-based research, its role in diseases such as cancer (colorectal cancer, breast cancer, acute myeloid leukaemia) has been revealed. Understanding Ddx21 provides potential for developing new strategies for disease treatment and prevention, especially in cancer, where its involvement in multiple oncogenic pathways makes it a promising target for further research [1-6, 8, 9, 10].