Context-dependent functions of ALKBH5: a mechanistic framework linking cellular stress responses, immune regulation,...

N⁶ -methyladenosine (m⁶A) is a major post-transcriptional RNA modification, and the demethylase ALKBH5 has emerged as a versatile but highly context-dependent regulator of RNA fate. This review integrates current evidence showing that ALKBH5 links epitranscriptomic control to cellular stress adaptation, genome maintenance, immune-cell function, viral infection, and therapeutic response. In DNA damage and cell-cycle regulation, ALKBH5 modulates checkpoint, repair, and apoptotic pathways, thereby influencing genome stability and sensitivity to radiotherapy or chemotherapy. In immune biology, it shapes γδ T-cell development, CD4⁺ T-cell pathogenicity, CD8⁺ T-cell infiltration, and tumor-immune crosstalk. In host-pathogen interactions, ALKBH5 can either enhance antiviral defense or promote viral persistence and latency, including HIV-1 reactivation, depending on the regulated transcript network. We propose that the biological output of ALKBH5 is determined by target transcript identity, cellular context, reader environment, and upstream regulatory signals. This framework positions ALKBH5 as both a mechanistic hub and a context-guided therapeutic target.