KIF4A stabilizes TDP43 to promote DNA damage repair and temozolomide resistance in glioblastoma.

Temozolomide (TMZ) resistance remains a major obstacle to effective glioblastoma (GBM) treatment and is closely linked to enhanced DNA damage repair. Kinesin family member 4A (KIF4A) has been implicated in tumor progression, but its role in TMZ resistance remains unclear. In this study, KIF4A and TAR DNA-binding protein 43 (TDP43) expression and prognostic significance were analyzed using The Cancer Genome Atlas glioma cohort and clinical specimens. KIF4A or TDP43 expression was manipulated in GSC23 and SU3 cells, followed by colony formation, apoptosis, comet, and western blot assays. Intracranial and subcutaneous xenograft models were established to evaluate TMZ responsiveness in vivo. Immunoprecipitation-mass spectrometry, reciprocal co-immunoprecipitation, proteasome inhibition, cycloheximide chase, ubiquitination, and rescue experiments were performed to investigate the molecular relationship between KIF4A and TDP43. KIF4A was upregulated in malignant glioma, TMZ-resistant GBM cells, and TMZ-treated cells, and was associated with higher WHO grade, unfavorable molecular features, and poor survival. Functionally, KIF4A overexpression enhanced clonogenic survival and reduced TMZ-induced DNA damage and apoptosis, whereas KIF4A knockdown increased TMZ sensitivity in vitro and suppressed tumor progression under TMZ treatment in vivo. Mechanistically, TDP43 was identified as a KIF4A-interacting protein, and KIF4A prolonged the half-life of TDP43 and reduced its ubiquitination, thereby limiting ubiquitin-proteasome-mediated degradation. TDP43 knockdown increased TMZ-induced DNA damage and apoptosis and partially reversed KIF4A-mediated TMZ resistance. Collectively, these findings demonstrate that KIF4A promotes TMZ resistance in GBM by stabilizing TDP43 and facilitating DNA damage resolution, suggesting that the KIF4A-TDP43 axis may represent a potential therapeutic target for improving TMZ sensitivity.