Herbal-derived phytochemicals in hepatocellular carcinoma: A review of molecular targets and tumor microenvironment interventions

Abstract

Hepatocellular carcinoma (HCC) is a health concern and stands as the most common primary liver malignancy. HCC frequently arises from chronic liver damage caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, prolonged alcohol consumption, and metabolic liver diseases, all of which contribute to the progressive accumulation of epigenetic and genetic alterations. These molecular changes drive uncontrolled proliferation, evasion of apoptosis, and immune resistance through the upregulation of programmed death ligand 1 (PD-L1) and remodeling of the tumor microenvironment (TME), together with enhanced angiogenesis, culminating in malignant transformation. Despite advancements in surgical and systemic interventions remain suboptimal, particularly in advanced stages where drug resistance and systemic toxicity pose significant limitations. In recent years, natural compounds derived from medicinal plants have garnered increasing interest due to their capacity to modulate multiple cancer-related pathways with comparatively lower toxicity. Alkaloids, flavonoids, saponins, and terpenoids exert anticancer effects by restricting tumor growth, inducing apoptosis and modulating Nrf2/Keap1 and VEGF/HIF-1α mediated pathways. Compounds such as curcumin, ginsenosides, withaferin A, and epigallocatechin gallate have demonstrated notable preclinical efficacy and enhanced the effectiveness of conventional therapies. This narrative review examines the molecular basis of HCC and the adjunctive potential of phytochemicals, emphasizing that extract variability, limited clinical evidence, and possible herb-drug interactions should be addressed to enable their safe and effective incorporation into standard therapy.

Keywords: Apoptosis, Angiogenesis, Oxidative stress, Tumor microenvironment, Drug resistance