Systems biology of Wnt signaling in glioma chemotherapy resistance: Integrating multi-omics mechanisms and emerging therapeutic vulnerabilities (Review).

Temozolomide (TMZ) resistance remains a key clinical challenge in treating glioma and a primary cause of tumor recurrence and therapeutic failure. Beyond well-established O6-methylguanine-DNA methyltransferase-mediated DNA repair, the Wnt signaling pathway, acting as a complex regulatory network, reinforces the chemoresistant phenotype through synergy with DNA repair systems and epigenetic reprogramming. The present review adopts a systems biology perspective to synthesize existing evidence, defining aberrant Wnt activation as a central integrative hub that drives TMZ resistance through a multi-tiered network. These mechanisms include enhanced DNA damage response, metabolic reprogramming, glioma stem cell maintenance and interactions with complex pathways such as PI3K/Akt and JAK/STAT. Current therapeutic strategies are summarized, ranging from small-molecule inhibitors and natural compounds to nanomedicine and cellular reprogramming, to propose treatment priorities for distinct resistance phenotypes. The present review aims to provide a reference for future translational research and the development of strategies to overcome chemoresistance in glioma.