Microwave dynamic therapy induces ferroptosis in colorectal cancer by targeting PTK2B to regulate STAT3-mediated GPX4 expression

Abstract Colorectal cancer (CRC) is a common malignant tumor of the digestive tract, and chemotherapy resistance along with adverse reactions during treatment present significant challenges in clinical practice. Therefore, there is an urgent need to find effective and low-toxicity therapeutic agents. Ferroptosis, a recently discovered form of cell death, has attracted attention as a potential new cancer treatment strategy. Microwave dynamic therapy (MWDT), as a promising anticancer agent, has been shown to significantly inhibit various malignancies, including CRC. However, the role of MWDT in ferroptosis and its underlying mechanisms have not been fully explored. In this study, we demonstrated that MWDT treatment significantly increased levels of lipid peroxidation (LPO), reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2 ⁺, while significantly decreasing glutathione (GSH) levels. Ferrostatin-1 partially inhibited these effects. Further research revealed that MWDT effectively inhibited tumor growth both in vitro and in vivo by inducing ferroptosis. At the molecular level, overexpression of PTK2B reversed the ferroptosis induced by MWDT. PTK2B interacted with STAT3 and enhanced its phosphorylation at Tyr705, promoting the nuclear translocation of p-STAT3 (Tyr705). In the nucleus, p-STAT3 bound to the GPX4 promoter region and promoted GPX4 transcription. MWDT inhibited PTK2B expression, suppressed STAT3 phosphorylation, and subsequently downregulated GPX4 transcription, thereby inducing ferroptosis. Our findings are the first to demonstrate that MWDT mediates ferroptosis in CRC via the PTK2B/STAT3/GPX4 axis, offering novel theoretical insights for its comprehensive treatment.