In conclusion, our integrated approach demonstrates that increased expression of lncRNA XIST3 in CRC confers a potent poor therapeutic efficacy, and that lncRNA XIST participated in 5FU resistance through promoting the expression of thymidylate synthase. Thus, specific silence oflncRNA XIST could be a future direction to develop a novel therapeutic strategy to overcome 5FU resistance of CRC patients.In addition, increased serum XIST level was associated with poor response and lower survival rate in CRC patients receiving 5FU-based treatment. However, nearly all patients receiving chemotherapy finally develop drug resistance, and this has been a major obstacle to improving the efficiency of colorectal cancer treatment. TS functions during the reductive methylation of deoxyuridine monophosphate to deoxythymidine monophosphate, with low level of folate 5,10-methylenetetrahydrofolate as the methyl donor.