Roles of m6A erasers FTO and ALKBH5 in drug resistance of hepatocellular carcinoma: mechanisms and clinical implications.

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor with substantial heterogeneity, posing formidable challenges to overcoming drug resistance. Accumulating evidence highlights the pivotal role of epitranscriptomic regulation, particularly N6-methyladenosine (m6A) modification, in reshaping tumor drug resistance. This review elaborates on the dual functions and mechanisms of m6A erasers FTO and ALKBH5 in HCC drug resistance. In cancer cells, these erasers post-transcriptionally regulate key transcripts to orchestrate metabolic reprogramming, enhance anti-apoptotic signaling, and sustain cancer stem cell properties. In the tumor microenvironment, they facilitate immune suppression by modulating chemokines and immune checkpoint molecules, driving the transition from immune-active to immune-suppressive tumors. Translational studies show FTO and ALKBH5 are promising dynamic biomarkers for predicting treatment responses and monitoring drug resistance. Small-molecule inhibitors targeting these erasers offer a potential strategy to surmount HCC drug resistance. Finally, we emphasize single-cell transcriptomics to dissect m6A heterogeneity in "resistance niches," constructing a comprehensive epitranscriptomic landscape for precise personalized HCC treatment.