CTSZ-Dependent Anoikis Resistance Enhances Malignant Characters of Glioblastoma via NF-kB Signaling

Glioblastoma (GBM) remains one of the most aggressive and therapy-resistant malignancies of the central nervous system, with anoikis resistance emerging as a critical facilitator of tumor invasion and therapeutic failure. In this study, we identified cathepsin Z (CTSZ) as a novel and pivotal regulator of anoikis resistance in GBM. Clinical data revealed significant elevation of CTSZ in GBM tissues, with its expression levels strongly correlating with adverse patient outcomes. Through comprehensive functional analysis, we demonstrated that genetic depletion of CTSZ substantially increased anoikis sensitivity in GBM cells while simultaneously attenuating multiple oncogenic characteristics. Mechanistically, we established that CTSZ-mediated anoikis resistance enhanced multiple malignancies of GBM through activation of the NF-kB signaling, as evidenced by impaired nuclear translocation of p65 following CTSZ knock-down. Taken together, our findings collectively position the CTSZ/NF-kB axis as a crucial determinant of GBM pathogenesis and highlight CTSZ as a promising therapeutic target for this devastating disease.