〔Abstract〕 Objective To explore the effect of FTO(fat mass and obesity-associated protein) and inhibitor on rituximab resistance in DLBCL(diffuse large B cell lymphoma). Methods Two cell lines derived from “double strike” lymphoma were selected, activated B-cell-like(ABC) OCI-LY8(LY8) and germinal center B-cell-like(GCB) OCI-LY18(LY18),and rituximab-resistant DLBCL cell lines(LY8R and LY18R) were constructed by “concentration gradient dosing method”.The CCK-8 method was used to detect the cell survival rate of different concentrations of rituximab after interfering with the parental and drug-resistant cells, and the half maximal inhibitory concentration(IC50) was calculated; AnnexinⅤ/PI double staining method was used to detect the apoptotic rate of parent cells and drug-resistant cells; qRT-RCR,immunofluorescence and Western blot were used to detect the expression of demethylase FTO in rituximab-resistant cells.The expression of FTO was inhibited by adding meclofenamic acid(MA) to drug-resistant cell lines, and the inhibition was verified by RT-qRCR and Western blot.The expression of c-Myc and CEBPA in drug-resistant strains after inhibiting FTO was detected by using Western blot. Results Compared with the parent cells, the expression of demethylase FTO and c-Myc increased, and the expression of CEBPA decreased in the rituximab-resistant cell lines, with statistical significance(P<0.01).After the drug-resistant cell lines treated with MA,the expression of FTO and c-Myc decreased and CEBPA increased, all with statistically significant differences(P<0.01). Conclusion The expression of FTO in drug-resistant DLBCL significantly increases, and MA inhibits the expression of FTO in drug-resistant cells, which may have therapeutic potential for rituximab-resistant DLBCL.