CREB1 activates GPX4 transcription and suppresses ferroptosis and thus contributes to platinum-based chemotherapy resistance in gastric cancer

Therapy resistance has become a common but intractable problem in the treatment of gastric cancer (GC). In this study, we demonstrated that GC patients with high expression of p-CREB1 and CREB1 were less sensitive to platinum-based chemotherapy. CREB1 promoted GC cell proliferation and platinum resistance in vitro . CREB1 could activate the transcription of GPX4, which suppresses ferroptosis and causes platinum resistance. The inhibition of GC cell proliferation and platinum resistance by ibrutinib was achieved by suppressing the phosphorylation of EGFR, PI3K, AKT, and CREB1 and inhibiting the EGFR–PI3K–AKT–CREB1 pathway. In PDO and CDX models, activation of the CREB1–GPX4 axis could effectively promote GC growth and platinum resistance by suppressing ferroptosis, and ibrutinib administration could enhance the sensitivity of CREB1-high-expression GC to platinum. Altogether, the findings illustrate that CREB1 activates the transcription of GPX4, inhibits ferroptosis, and causes platinum resistance in GC, while the CREB1 inhibitor ibrutinib reduces GC cell proliferation and reverses platinum resistance by suppressing EGFR, PI3K, AKT, and CREB1 phosphorylation. This will provide a reliable theoretical basis for individualized comprehensive GC treatment.