Natural Bioactive Compounds Targeting the Wnt/β-Catenin Pathway for the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with limited treatment options and poor prognosis. The Wnt/β-catenin signaling pathway is a key regulator of cellular proliferation, differentiation, and stem cell maintenance, and is frequently dysregulated in HCC, contributing to tumor progression, metastasis, and drug resistance. Natural bioactive compounds (NBCs) have emerged as promising treatments due to their multi-targeted mechanisms, low toxicity, and ability to modulate key oncogenic pathways. This review examines the potential of NBCs to target the Wnt/β-catenin pathway in HCC. Compounds such as curcumin, emodin, gallic acid, and ginsenosides exhibit anti-tumor effects by inhibiting β-catenin nuclear translocation, inducing autophagy, suppressing angiogenesis, and modulating the tumor microenvironment. For example, curcumin inhibits HCC cell proliferation and invasion by downregulating lncRNA expression and EMT markers, thereby inactivating the Wnt/β-catenin signaling pathway. Additionally, alkaloids like tetrandrine and toosendanin reduce metastasis through pathway-specific inhibition and epigenetic modulation. These compounds demonstrate potential as standalone therapies, and also in combination with conventional treatments like sorafenib by enhancing the effectiveness and overcoming resistance. However, challenges such as limited bioavailability, stability, and the intricate interplay of the Wnt/β-catenin pathway with other signaling pathways highlights the need for advanced delivery systems and combination strategies. In conclusion, future research should prioritize clinical validation, precision medicine approaches, and exploration of the role of NBCs in cancer stem cell regulation. Collectively, NBCs targeting the Wnt/β-catenin pathway offer a novel, safer, and multi-faceted approach for improving HCC treatment outcomes, paving the way for their integration into standard therapeutic regimens.