Targeting aldolase B to disrupt the β-Catenin/TCF4 axis and inhibit hepatocellular carcinoma progression: A novel small-molecule therapeutic strategy

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Aldolase B (ALDOB) acts as a tumor suppressor in hepatocellular carcinoma (HCC), yet its role in metastasis remains poorly defined, and the development of specific ALDOB modulators has posed a major challenge. Through genetic manipulation, this study establishes that ALDOB overexpression suppresses HCC proliferation and metastasis both in vitro and in vivo via dual mechanisms: inhibiting the pentose phosphate pathway and, following nuclear translocation, disrupting β-catenin/ transcription factor 4 (TCF4) interaction to repress oncogene transcription. An EED277-279AAA mutation disrupts the ALDOB–β-catenin interaction, thereby abolishing its anti-HCC effects. Leveraging these mechanisms, we identified 1-(3,4-dimethoxyphenyl)-3-(2-hydroxy-4,6-dimethoxyphenyl)propane-1,3-dione (MD33), a novel ALDOB modulator with potent anti-HCC activity. MD33 binds the ALDOB active sites, enhances ALDOB/β-catenin complex formation, promotes Akt dephosphorylation, and thereby effectively curbs tumor progression. These results highlight the central role of ALDOB in HCC pathogenesis and its potential as a therapeutic target amenable to both genetic and pharmacological intervention.