ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1616975
Dual-Edged Mechanisms of α-Tomatine in Hepatocellular Carcinoma by Suppression of Wnt/β-Catenin signaling versus RelB-Driven Resistance in Tumor Therapy
Provisionally accepted
- East China Normal University, Shanghai, China
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The plant-derived steroidal alkaloid α-tomatine has emerged as a promising pancancer therapeutic agent, its multifaceted biological effects in HCC remain unexplored. This study aims to decipher α-tomatine's molecular duality in HCC, resolving its paradoxical capacity to simultaneously activate tumor-suppressive signaling and provoke chemoresistance networks, ultimately establishing synergistic phytotherapy strategies.Methods: HepG2 and SMMC-7721 hepatocellular carcinoma cells were exposed to α-tomatine to evaluate dose-dependent effects on proliferation, migration/invasion, and cell cycle distribution. Transcriptomic profiling via RNA sequencing identified dysregulated pathways. Pharmacological interventions using Wnt3a (activation) and XAV939 (inhibition) modulated Wnt/β-catenin signaling, while CRISPR/Cas9-mediated RelB knockout and plasmid-based overexpression established isogenic cell models. These interventions were subsequently applied in BALB/c nude mouse xenografts, where tumor volume was longitudinally monitored during α-tomatine treatment. Results: α-Tomatine demonstrated dose-dependent suppression of hepatocellular carcinoma cell proliferation, migration, and invasion, concomitant with G2/M phase arrest. Mechanistically, it exerted Wnt/β-catenin inhibition via β-catenin phosphorylation/degradation while paradoxically inducing RelB-mediated reduction of anti-tumor activity. Wnt activation attenuated therapeutic effects, whereas Wnt inhibitors enhanced efficacy. Genetic RelB ablation potentiated α-tomatine's anti-tumor activity, contrasting with resistance in RelB-overexpressing models. Xenografts confirmed enhanced suppression in RelB-deficient tumors. Conclusion: This plant-derived alkaloid exerts anti-HCC effects through Wnt pathway modulation, while compensatory RelB activation constrains therapeutic outcomes. Strategic RelB co-targeting establishes a dual pathway phytotherapy paradigm, synergistically merging botanical pharmacodynamics with precision oncology.
Keywords: Bianhong Zhang, No.500, Dongchuan Road, Minhang district, α-Tomatine, Hepatocellular Carcinoma, Wnt/β-catenin signaling, RelB
Received: 29 Apr 2025; Accepted: 01 Aug 2025.
Copyright: © 2025 Zhang, Wang, Xu and Yuan. 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: Bianhong Zhang, East China Normal University, Shanghai, China
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