XAV-939

In vitro, JPI-547 and olaparib more effectively reduced cell survival in PTEN-deficient cells, and combined treatment with olaparib and the TNKS inhibitor XAV-939 induced synergistic cytotoxicity with elevated DNA double-strand breaks. PTEN knockdown further showed enhanced vulnerability to combined targeting. These findings show that JPI-547 enhances antitumor efficacy in PTEN-deficient EC by disrupting DNA repair pathways and Wnt signalling, supporting dual PARP/TNKS inhibition as a potential therapeutic strategy and providing a rationale for further clinical evaluation.

KIF11 can promote the malignant phenotype and DDP resistance of tumor cells by activating the Wnt/β-catenin signaling pathway in OC. Therefore, KIF11 has the potential to serve as a biomarker for predicting OC progression and the efficacy of DDP treatment.

Mechanistically, PDRG1 activated Wnt/β-catenin signaling, elevating levels of β-catenin, c-Myc, and phosphorylated GSK-3β, and the oncogenic effects of PDRG1 were reversed by the Wnt pathway inhibitor XAV939...The pro-tumor effects of SP1 were rescued by PDRG1 silencing, indicating that SP1 acts through PDRG1. Collectively, our study identifies SP1 as an upstream transcriptional activator of PDRG1 and defines the SP1/PDRG1/Wnt/β-catenin axis as a key regulatory pathway promoting HCC progression, suggesting its potential as a prognostic biomarker and therapeutic target.

In vivo, the combination of L-asparaginase and doxorubicin, as well as treatment with XAV-939, significantly inhibited tumor growth, whereas NAC attenuated these effects. In conclusion, glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma. Mechanistically, this chemosensitizing effect is mediated by downregulation of GLUD1, which promotes intracellular ROS accumulation and subsequently suppresses Wnt/β-catenin signaling.

Compared to XAV939, LF3 more effectively inhibits nuclear β-catenin, might resulting in lower off-target toxicity and making it a favorable clinical candidate for targeting GBCs.

Moreover, the Wnt/β-catenin inhibitor XAV939 reduced lactate production and H3K18la levels. Here, we demonstrate that the glycolysis/H3K18la/TK1/β-catenin positive feedback loop exacerbates dysfunction in OSCC initiation. These findings reveal a novel link between epigenetic regulation and lactate-driven metabolic reprogramming, which may lead to the development of innovative lactylation treatment approaches for OSCC therapy.

Following transfection, the Wnt signaling pathway inhibitor XAV-939 and agonist SKL2001 were administered to the KLF4-overexpressing cells...Results demonstrated that KLF4 overexpression inhibits EMT in gastric cancer cells through the Wnt/β-catenin signaling pathway. Thus, this study concludes that KLF4 may modulate EMT in gastric cancer cells via the Wnt/β-catenin pathway.

Combining Everolimus with the Wnt inhibitor XAV-939 slashed viability and invasion in resistant cells. Its loss defines a metastatic, therapy-resistant subtype targetable by dual mTOR/Wnt blockade. Therefore, MAGI3 expression may stratify patients for personalized therapy.

DVL2 knockdown or XAV-939 significantly abrogates above effects mediated by IFIT3 (p <0.05). Overall, we demonstrated a novel signal transduction pathway where IFIT3 interacts with DVL2 to stabilize cytosolic β-catenin and promote β-catenin nuclear translocation via DVL2 phosphorylation, enhancing canonical WNT signaling activity and providing a potential target for clinical intervention in LUSC and LCLC.

Functional validation experiments show that conditional deletion of IRGM1 or pharmacological inhibition of downstream signaling using XAV-939 markedly attenuates S. salivarius-induced NET formation, indicating the requirement of this pathway in the metastatic process. Furthermore, clinical sample analyses reveal that S. salivarius is significantly enriched in the tongue coating and feces of patients with CRC and is elevated within the tumor microenvironment. Together, these findings identify IRGM1-IQGAP1-mediated Wnt5a-PI3K/AKT signaling as a mechanistic link between oral microbiota and neutrophil-driven immune responses in cancer metastasis.

Although XAV939 is a known TNKS-1 inhibitor, it demonstrated comparatively reduced efficacy across binding and stability metrics. In conclusion, this integrative computational evidence supports microbial-derived compounds as promising natural candidates for TNKS-1 inhibition, offering a new avenue for in vivo validation and structure-guided discovery of next-generation microbe-based therapeutics for colorectal cancer. The online version contains supplementary material available at 10.1007/s40203-026-00585-9.

In vitro, XAV939 suppressed β-catenin-driven aerobic glycolysis in TNBC cells, downregulating β-catenin and glycolytic proteins, reducing glycolytic activity, and impairing aggressive phenotypes (proliferation, migration, invasion, clonogenicity).ConclusionOverall, our results highlight the crucial role of β-catenin in controlling aerobic glycolysis via regulation of key glycolytic proteins, thereby positively driving the progression and metastasis of TNBCs. Additionally, our data strongly establish that XAV939 effectively inhibits glycolytic phenotype, thereby suggesting its therapeutic potential in TNBC patients.