Repression of FOSL1 augments ferroptosis to overcome oxaliplatin resistance in colorectal cancer by acting on SRSF2.

BACKGROUND

Chemotherapy resistance, particularly resistance to oxaliplatin, remains a major clinical challenge in the treatment of colorectal cancer (CRC). Ferroptosis, a newly characterized form of regulated cell death, has emerged as a potential mechanism for overcoming chemotherapy resistance. The transcription factor FOSL1 has been implicated in CRC progression and chemoresistance; however, its role in ferroptosis is not well defined.

METHODS

Gene and protein expression levels were assessed by quantitative real-time PCR (qRT-PCR) and western blotting, respectively. Malondialdehyde (MDA), glutathione (GSH), and intracellular iron levels were measured using ELISA. Lipid peroxidation was evaluated using the C11-BODIPY 581/591 probe. Cell viability and cell death were determined by the CCK-8 assay and Calcein-AM/propidium iodide (PI) double staining, respectively. The interaction between FOSL1 and the SRSF2 promoter was examined using dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays.

RESULTS

FOSL1 was significantly overexpressed in CRC tissues and oxaliplatin-resistant CRC cells and was negatively correlated with the ferroptosis-related proteins GPX4, SLC7A11, and FTH1. Silencing of FOSL1 reduced oxaliplatin resistance in CRC cells by promoting ferroptosis. Mechanistically, FOSL1 transcriptionally activated SRSF2 expression. Overexpression of SRSF2 reversed the ferroptosis-promoting and oxaliplatin resistance-suppressing effects induced by FOSL1 knockdown.

CONCLUSION

FOSL1 promotes oxaliplatin resistance in CRC by suppressing ferroptosis through the upregulation of SRSF2. Targeting FOSL1 may represent a novel therapeutic strategy to overcome oxaliplatin resistance in colorectal cancer.