Current Therapeutic Strategies, Recent Advances and the Emerging Potential of Natural Products in Hepatocellular...

Hepatocellular carcinoma (HCC) accounts for 75%-85% of all primary liver cancers and remains one of the leading causes of cancer-related mortality worldwide. Despite advances in diagnosis and systemic therapies, the clinical management of HCC is hindered by limited therapeutic efficacy, drug resistance, systemic toxicity and high recurrence rates. Consequently, there is a pressing need for alternative and complementary treatment strategies. Natural products, particularly plant-derived phytochemicals, have long been valued for their diverse pharmacological activities and represent a promising source of novel anticancer agents. This review critically examines current HCC treatment modalities and their limitations, while highlighting the therapeutic potential of phytochemicals based on preclinical and clinical evidence, with emphasis on their molecular mechanisms of action. Furthermore, recent advances in nanotechnology-based drug delivery systems are discussed as a potential way to overcome key translational barriers associated with phytochemicals, including poor bioavailability, limited tumour selectivity and suboptimal pharmacokinetics. The integration of phytochemistry with nanomedicine offers a powerful strategy to enhance therapeutic efficacy, reduce systemic toxicity and improve clinical translation. We identify apoptosis induction, suppression of PI3K/Akt, MAPK, STAT3, NF-κB and HIF-1 signalling, and modulation of oxidative stress and metastasis as the dominant anti-HCC mechanisms of major phytochemicals. In addition, we highlight nanotechnology-based delivery systems as a key translational strategy to improve solubility, tumour selectivity and therapeutic performance of these compounds. Collectively, this review underscores the promise of plant-derived compounds, either alone or in combination with existing therapies, as the next generation of HCC therapeutics.