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ORIGINAL RESEARCH article

Front. Oncol.

Sec. Cancer Molecular Targets and Therapeutics

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1641979

This article is part of the Research TopicInnovative Drug Combinations for Enhanced Solid Tumor Treatment EfficacyView all 8 articles

Diaryl Pyrimidine guanidine Suppresses Hepatocellular Carcinoma Cell Stemness by Targeting β-catenin Signaling

Provisionally accepted
  • 1First Hospital, Peking University, Beijing, China
  • 2Yunnan University, Kunming, China
  • 3Peking University First Hospital, Beijing, China

The final, formatted version of the article will be published soon.

Background: Liver cancer remains a major global health burden, with hepatocellular carcinoma (HCC) accounting for approximately 80% of liver cancer cases. Cancer stem cells (CSCs) play a critical role in HCC initiation, progression, metastasis, and resistance to therapy, making them critical targets for novel therapeutic interventions.However, effective agents specifically targeting CSCs in HCC remain limited. The objective of this study was to identify and characterize novel small molecules that inhibit CSCs properties and overcome drug resistance in HCC.: Functional assays assessed the effects of C504244 on tumor sphere formation, cancer cell proliferation, and migration. RNA sequencing was conducted on C504244-treated HCC cells to investigate changes in gene expression profiles. Downstream targets of the Wnt signaling pathway were analyzed to determine pathway inhibition. Co-immunoprecipitation (Co-IP) was performed to assess whether C504244 disrupts the interaction between β-catenin and Transcription Factor 4 (TCF4) in HCC cells. Lenvatinib-resistant HCC cell lines were used to evaluate the combinatorial efficacy of C504244 and Lenvatinib in vitro and in vivo. Results: C504244 significantly suppressed tumor sphere formation, proliferation, and migration of HCC cells. Transcriptome analysis revealed that C504244 treatment led to significant inhibition of the Wnt signaling pathway, with corresponding downregulation of downstream target gene expression. Mechanistically, C504244 disrupted the βcatenin/TCF4 complex formation, which may contribute to reduced transcriptional activity. Since β-catenin signaling is hyperactivated in Lenvatinib-resistant HCC cells, C504244 was tested in combination with Lenvatinib and found to markedly sensitize these resistant cells to Lenvatinib treatment both in vitro and in vivo.Conclusions: C504244 represents a promising agent that effectively inhibits β-catenin signaling, thereby impairing CSCs properties and reversing Lenvatinib resistance in HCC cells. These findings suggest that C504244 may serve as a potential therapeutic agent for HCC.

Keywords: Diaryl Pyrimidine guanidine, CSCs, HCC, β-catenin/TCF4, Lenvatinib resistance, combination treatment

Received: 05 Jun 2025; Accepted: 05 Aug 2025.

Copyright: © 2025 Xuechun, Ni, Cheng, Liang, Zhang, Xiao and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Ruihan Zhang, Yunnan University, Kunming, China
Weilie Xiao, Yunnan University, Kunming, China
Rong Liu, First Hospital, Peking University, Beijing, China

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