PRSS23 orchestrates nonclassical ferroptosis resistance in glioblastoma by modulating chromatin accessibility via the NCAPD3/YY1/MBOAT2 axis

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Glioblastoma is the most aggressive primary malignancy of the central nervous system. Emerging evidence indicates that hypoxia-induced ferroptosis resistance is a key factor in therapeutic resistance and solid tumor growth. Here, we reveal the PRSS23–NCAPD3/YY1/MBOAT2 signaling axis as a critical mediator of noncanonical ferroptosis resistance in glioblastoma. Machine learning was applied to the analysis of TCGA/CCGA datasets, and PRSS23 was identified as a critical glioblastoma-associated protease, with elevated expression in hypoxic tumor regions correlating with poor patient prognosis. Functional assays confirmed the impact of PRSS23 on cell proliferation, while co-immunoprecipitation and subcellular localization studies demonstrated the nuclear translocation of PRSS23 and its interaction with the chromatin remodeling factor NCAPD3. Multi-omics integration (ATAC-seq, RNA-seq) revealed that hypoxia-induced PRSS23–NCAPD3 cleavage promoted chromatin accessibility, driving transcriptional activation of the YY1-MBOAT2 axis. Lipidomic analysis further linked this pathway to reduced membrane polyunsaturated fatty acid/monounsaturated fatty acid ratios, establishing a mechanism of atypical ferroptosis resistance. In murine models, pharmacological inhibition of PRSS23 via SPINK1 and disruption of the PRSS23–NCAPD3 interaction using the Pa-125 TAT peptide enhanced ferroptosis sensitivity, suppressed tumor growth, and prolonged survival. Collectively, these results highlight the critical role of PRSS23 in enhancing nonclassical ferroptosis resistance in hypoxia via the NCAPD3/YY1/MBOAT2 axis, which drives glioblastoma progression. SPINK1 and the Pa-125 TAT peptide may serve as treatment reagents to disrupt this mechanism.