Serine/arginine-rich splicing factor 1 inhibits ferroptosis and promotes glycolysis in endometrial cancer via activating mTOR and β-catenin.

Serine/arginine-rich splicing factor 1 (SRSF1) is a pre-mRNA-splicing factor functioning as an oncogene in multiple cancers. However, the biological roles of SRSF1 in endometrial cancer (EC) have not been explored. Here we demonstrated its pivotal function and the regulatory mechanism in regulating ferroptosis and glycolysis in EC. Results showed that SRSF1 inhibited ferroptosis in EC cells, indicated by decreased cell death rate, lipid peroxidation and Fe2 + concentration. SRSF1 accelerated glycolysis in EC cells, evidenced by enhanced glucose uptake, lactate production and adenosine triphosphate production. Mechanistically, SRSF1 elevated the levels of phosphorylated mTOR and β-catenin in EC cells. Besides, the regulation of glycolytic enzyme proteins by SRSF1 in EC cells was dependent on mTOR and β-catenin. Furthermore, rescue assays unveiled that mTOR, β-catenin, and glycolysis involved in the regulatory function of SRSF1 on ferroptosis in EC cells. Finally, animal study proved that SRSF1 knockdown restrained in vivo tumor growth and potentiated the antitumor efficacy of ferroptosis inducer through glycolysis inhibition. In conclusion, the present study uncovered that SRSF1 acts as a tumor promoter in EC through activating mTOR and β-catenin to inhibit ferroptosis and facilitate glycolysis, proposing a therapeutic target for EC.