Mechanistic insights into the role of RNA demethylase ALKBH5 in malignant tumor therapy.

m6A RNA methylation represents the most prevalent epitranscriptomic modification and modulates diverse dimensions of RNA metabolism. As a dynamic and reversible post-transcriptional mark, m6A is broadly distributed across multiple RNA types, including mRNA, ribosomal RNA (rRNA), microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), and small nuclear RNA (snRNA). ALKB homolog 5 (ALKBH5), an m6A demethylase, has been extensively characterized for its involvement in tumorigenesis and progression through the removal of methylated modification from RNA, subsequently influencing RNA metabolism and gene expression regulation. A growing body of evidence indicates that ALKBH5 contributes to the therapeutic response in various cancers. Its aberrant expression is frequently observed across malignancies, where it modulates oncoprotein levels, promotes tumor initiation, and accelerates cancer cell proliferation, progression, and metastasis. Nevertheless, its implications for therapy responsiveness and the emergence of drug resistance remain poorly understood. This review centers on ALKBH5-mediated regulatory pathways and mechanisms in the contexts of chemotherapy, radiotherapy, and immunotherapy in malignancies, while also evaluating the therapeutic relevance of ALKBH5 as a molecular target and the potential of its pharmacological inhibitors.