ALKBH5 in development: decoding the multifaceted roles of m⁶A demethylation in biological processes

N⁶-methyladenosine (m⁶A), an abundant internal RNA modification in eukaryotes, serves as a dynamic post-transcriptional regulator of gene expression by influencing RNA splicing, stability, translation, and decay. This reversible epitranscriptomic mechanism, which is mediated by methyltransferase (writers), demethylase (erasers), and m⁶A-binding proteins (readers), is pivotal in diverse biological contexts. Among m⁶A erasers, alkylation repair homolog protein 5 (ALKBH5), an Fe(II)/α-ketoglutarate-dependent dioxygenase, is the second to be discovered and one of the most significant demethylases. Mounting evidence underscores ALKBH5's role in modulating developmental programming, where it coordinates processes such as lineage specification, organogenesis, and tissue homeostasis. This review systematically deciphers the multifaceted contributions of ALKBH5-mediated m⁶A demethylation to developmental biology. We synthesize recent advances elucidating how ALKBH5-driven m⁶A erasure dynamically regulates transcriptomic rewiring during embryogenesis, reproductive development, cardiac development, central nervous system development, immune system development, pancreatic organogenesis, osteogenic/odontogenic differentiation, adipogenesis, and angiogenesis. These revelations not only deepen our understanding of epitranscriptomic regulation in ontogeny but also illuminate therapeutic avenues for developmental anomalies and regenerative medicine.