Shahrekord University of Medical Sciences Journal of Herbmed Pharmacology 2345-5004 15 1 2026 01 01 Herbal-derived phytochemicals in hepatocellular carcinoma: A review of molecular targets and tumor microenvironment interventions 11 26 10.34172/jhp.2026.53276 EN Jithin Mathew https://orcid.org/0000-0002-1545-4342 Shakkeela Yusuf Erattil Ahammed https://orcid.org/0000-0002-4666-5978 Ghada Ben Salah https://orcid.org/0000-0002-5886-1968 Abir Elghazaly https://orcid.org/0000-0002-6774-1079 Syeda Ayesha Farhana https://orcid.org/0000-0001-8154-7718 Shalam M Hussain https://orcid.org/0000-0002-2398-5485 Journal Article 10.34172/jhp.2026.53276 2025 07 12 2025 10 11 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.