PFKFB3 confers cisplatin resistance in gastric cancer by inhibiting ferroptosis through SLC7A11/xCT dephosphorylation.

Cisplatin-based combination chemotherapy is a cornerstone of perioperative and adjuvant therapies for gastric cancer (GC). However, cisplatin resistance resulting from repeated treatment limits its clinical application. PFKFB3 (6-phosphofructo-2-kinase), an isoenzyme of the PFKFB family, functions as a vital regulator of glycolysis and is involved in multiple cancer-related processes, including carcinogenesis, proliferation, metastasis, and drug resistance. In this study, we aimed to investigate the role of PFKFB3 in cisplatin resistance in gastric cancer and explore its underlying mechanisms. We found that PFKFB3 is significantly increased in gastric cancer tissues and is associated with a poor prognosis in patients with GC. PFKFB3 overexpression promoted gastric cancer proliferation and conferred cisplatin resistance both in vitro and in vivo. Interestingly, we identified that PFKFB3 serves as a negative regulator of ferroptosis, thereby rendering GC resistant to cisplatin. Mechanistically, our results demonstrated that PFKFB3 could suppress ferroptosis by directly dephosphorylating SLC7A11/xCT serine 26 (S26) via its 246-520 region. The combination of cisplatin and Erastin, a ferroptosis inducer, could synergistically enhance the anti-tumor effect of cisplatin in a subcutaneous tumor mouse model. Our findings demonstrate that PFKFB3 desensitizes gastric cancer to cisplatin by inhibiting ferroptosis through SLC7A11/xCT dephosphorylation, suggesting PFKFB3 inhibition as a potential strategy to overcome cisplatin resistance in GC patients.