Mechanistic insights into TXNDC17-mediated ferroptosis suppression in glioblastoma progression.

Abstract

Background: Glioblastoma (GBM) is a lethal brain tumor with limited treatment options. Molecular targeted therapy is considered safe and promising for GBM. Ferroptosis is regulated by lipid, iron and cysteine metabolism. Induction of ferroptosis is a promising strategy.

Methods: Integrated bioinformatics analysis of GBM datasets (TCGA) and RNA-seq data from human gliomas was used to identify candidate genes. TXNDC17 expression was validated in glioma tissues and cell lines by qPCR, western blotting and immunofluorescence. In vitro functional assays (CCK-8, wound healing, Transwell) were performed to assess proliferation, migration and invasion following TXNDC17 knockdown (siRNA). Ferroptosis sensitivity was evaluated by measuring GSH and LPO levels after TXNDC17 manipulation. GPX4 rescue experiments were conducted. In vivo therapeutic efficacy was examined in orthotopic GBM mouse models using TXNDC17-silenced cells treated with RSL3 (an inhibitor of GPX4) with tumor growth monitored by bioluminescence.

Results: Bioinformatics analysis identified TXNDC17 as a key prognostic risk factor. Molecular validation confirmed grade-dependent TXNDC17 overexpression in gliomas. TXNDC17 knockdown markedly suppressed GBM cell proliferation, migration and invasion. Mechanistically, TXNDC17 promoted glioma progression by regulating ferroptosis, specifically through cooperation with GPX4 to inhibit ferroptosis. Knockdown reduced GPX4 expression, thereby increasing ferroptosis sensitivity. GPX4 overexpression rescued proliferation and invasion defects caused by TXNDC17 knockdown, confirming its functional dependence. TXNDC17 silencing combined with RSL3 synergistically suppressed GBM growth in vitro.

Conclusion: TXNDC17 functions as a novel oncoprotein and ferroptosis suppressor in GBM by regulating GPX4 and promoting tumor progression. Targeting the TXNDC17-GPX4 axis through TXNDC17 silencing and RSL3 treatment represents a potent synergistic therapeutic strategy.