Ferroptosis suppression by MYC confers oxaliplatin resistance in colorectal cancer via FTH1 and GPX4.

PURPOSE: Oxaliplatin resistance remains a major obstacle in the treatment of colorectal cancer (CRC). This study aimed to determine whether MYC contributes to oxaliplatin resistance by regulating ferroptosis and to clarify the downstream mechanisms involving FTH1 and GPX4.

METHODS

Parental CRC cell lines, including HCT116, HT-29 and SW480, together with oxaliplatin-resistant HCT116-R cells, were used. MYC expression was manipulated by knockdown or overexpression. Oxaliplatin sensitivity was evaluated using CCK-8 assays and IC50 analysis. Intracellular Fe2⁺ and reactive oxygen species (ROS) levels were measured to assess ferroptosis-associated changes. RT-qPCR and western blotting were performed to examine gene and protein expression. Chromatin immunoprecipitation-qPCR and dual-luciferase reporter assays were used to investigate the transcriptional regulation of FTH1 and GPX4 by MYC. Rescue experiments with FTH1 or GPX4 overexpression and sorafenib treatment were also conducted.

RESULTS

MYC knockdown significantly increased oxaliplatin sensitivity in both parental and resistant CRC cells and elevated intracellular Fe2⁺ and ROS levels. MYC directly bound to the promoter regions of FTH1 and GPX4 and enhanced their transcriptional activity. Downregulation of MYC reduced FTH1 and GPX4 expression, whereas re-expression of either FTH1 or GPX4 partially restored oxaliplatin resistance. Sorafenib further enhanced oxaliplatin sensitivity in resistant cells.

CONCLUSION

MYC promotes oxaliplatin resistance in CRC cells, at least in part, by transcriptionally upregulating FTH1 and GPX4 and suppressing ferroptosis-associated cell death. The MYC-FTH1/GPX4-ferroptosis axis may represent a potential therapeutic target for overcoming oxaliplatin resistance in CRC.