PFKFB3 attenuates cisplatin-induced ferroptosis in gastric cancer via dephosphorylation of SLC7A11

Abstract 6-phosphofructo-2-kinase (PFKFB3) is an isoenzyme of the PFKFB family, of which numerous studies have revealed the involvement in tumorigenesis and malignant behaviors in a non-glycolysis-dependent manner. Based on our findings of PFKFB3 in trastuzumab resistance, interestingly, we have found that PFKFB3 significantly attenuated cisplatin cytotoxicity both in vivo and in vitro. We demonstrated that overexpression of PFKFB3 markedly inhibited Erastin- and cisplatin-induced ferroptotic cell death. We further showed that Cystine/glutamate antiporter (xCT) interacts with the phosphatase domain of PFKFB3 and can be dephosphorylated at serine 26 (S26) by PFKFB3. The dephosphorylation of S26 greatly enhances xCT transporter activity, is critical for the production of GSH, and inhibits cisplatin-induced ferroptosis. Notably, erastin reversed PFKFB3-mediated resistance to cisplatinboth in vivo and in vitro. Collectively, our findings open a door to uncover how PFKFB3 promotes cisplatin resistance and may provide a potential target for gastric cancer treatment.