N6-methyladenosine (m6A) methylation is a dynamic epitranscriptional modification controlled by the combined action of specific writers, erasers and readers (effectors) markedly impacting RNA metabolism. m6A has been reported to participate in the development of hepatocellular carcinoma (HCC). However, its role in HCC drug resistance remains unclear. Reanalyzing data of a pharmacogenomic study in HCC we identified a high number of m6A effectors whose expression was significantly associated to drugs resistance or sensitivity. We hypothesized that we may revert cell resistance to the drugs by altering the fate of modified RNAs through the perturbation of specific m6A effectors. Selecting three different HCC cell lines (HepG2, Hep3B, Snu475), we shortlisted 3 different combinations of m6A effectors and drugs. We demonstrated that the knockdown (through RNAi and CRISPR-I) of some specific m6A effectors (ALKBH5, VIRMA, YTHDF2) synergizes with various chemotherapy drugs, and this combinatorial effect leads to an increase in the sensitivity of the cells to the given drug. Furthermore, ALKBH5 is markedly and consistently upregulated after following the drug treatment in all the cell lines tested, suggesting a direct involvement of the effector in the chemotherapy drug response pathway. Finally, the knockdown of ALKBH5 leads also to changes in m6A bulk levels in the different cell lines, suggesting that its role is related to its catalytic function in the m6A machinery. We are currently characterizing through Nanopore sequencing whether m6A-dependent alterations of the RNA metabolism are central in the drug resistance. Ulltimately these data might disclose novel molecular mechanisms, through which epitranscriptional alterations impact on drug resistance and shape HCC aberrant transcriptional programs.