FOXP4 maintains redox homeostasis in medulloblastoma via upregulation of SLC7A11 to suppress ferroptosis
TL;DR
This study demonstrates that FOXP4 is overexpressed in MB, especially in the high-risk Group 3 (G3) subtype, and correlates with poor patient prognosis, and provides a mechanistic rationale for targeting this pathway to enhance the efficacy of ferroptosis-inducing therapies, such as sorafenib, in high-risk MB.
Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor and remains a major therapeutic challenge due to its aggressive behavior, high risk of metastasis, and limited treatment options for high-risk subgroups. The transcription factor FOXP4, a member of the forkhead box (FOX) family, has been implicated in tumorigenesis, including MB progression. However, the functional role of FOXP4 and the underlying mechanisms-particularly in regulating cell death pathways such as ferroptosis-remain largely unknown. In this study, we demonstrate that FOXP4 is overexpressed in MB, especially in the high-risk Group 3 (G3) subtype, and correlates with poor patient prognosis. Functionally, FOXP4 promotes tumor cell proliferation and protects against ferroptosis by directly upregulating SLC7A11 , the catalytic subunit of the cystine/glutamate antiporter system xc⁻. Mechanistically, FOXP4 binds to the SLC7A11 promoter to enhance cystine uptake and glutathione biosynthesis, thereby suppressing iron-dependent lipid peroxidation. Inhibition of FOXP4 sensitizes MB cells and xenograft tumors to ferroptosis, as evidenced by increased lipid reactive oxygen species (ROS) and 4-hydroxynonenal (4-HNE) accumulation. Our findings identify the FOXP4–SLC7A11 axis as a key regulator of redox homeostasis in MB and provide a mechanistic rationale for targeting this pathway to enhance the efficacy of ferroptosis-inducing therapies, such as sorafenib, in high-risk MB.