Jithin Mathew
1* 
, Shakkeela Yusuf Erattil Ahammed
2 , Ghada Ben Salah
3 , Abir Elghazaly
4 , Syeda Ayesha Farhana
5 , Shalam M Hussain
6 1 Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences, Department of Pharmacology, Mangalore, Karnataka, India
2 Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah, Qassim, Saudi Arabia
3 Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraidah, Qassim, Saudi Arabia
4 Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraidah, Qassim, Saudi Arabia
5 Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraidah, Qassim, Saudi Arabia
6 Department of Clinical Pharmacy, College of Health Sciences and Nursing, Al-Rayan Colleges, AL-Madinah AL-Munawarah, Saudi Arabia
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.
Implication for health policy/practice/research/medical education:
The study highlights the value of affordable, safe therapeutic alternatives for policy, supports the use of natural compounds in liver cancer, emphasizes the need for further research on bioactive molecules, and encourages inclusion of evidence-based traditional medicine in medical education for integrative healthcare.
Please cite this paper as: Mathew J, Erattil Ahammed SY, Salah GB, Elghazaly A, Farhana SA, Hussain SM. Herbal-derived phytochemicals in hepatocellular carcinoma: A review of molecular targets and tumor microenvironment interventions. J Herbmed Pharmacol. 2026;15(1):11-26. doi: 10.34172/jhp.2026.53276.