Targeting Chemical-induced Hepatocellular Carcinoma: Ameliorative Potential of Natural Compounds with Focus on...

Hepatocellular carcinoma (HCC), the predominant form of primary liver malignancy, remains a major global health concern owing to its aggressive progression, limited therapeutic efficacy, and high fatality rate. A significant proportion of HCC arises from chronic exposure to chemical carcinogens, which trigger hepatocarcinogenesis through oxidative stress, DNA damage, and dysregulation of signalling networks. Natural compounds, particularly beta-carboline alkaloids, are emerging as safer, multi-targeted candidates with promising hepatoprotective and anticancer potential. This review has critically evaluated chemical-induced hepatocarcinogenesis and the therapeutic relevance of beta-carbolines in HCC.

A systematic literature survey was conducted using PubMed, Scopus, and Web of Science databases, emphasizing studies on chemical-induced HCC, natural hepatoprotective compounds, and beta-carboline derivatives. Mechanistic, pharmacological, and preclinical data were extracted and analyzed.

Carcinogens, such as diethylnitrosamine (DEN), aflatoxin B1, and carbon tetrachloride (CCl₄), promote HCC by inducing oxidative stress, genotoxicity, and perturbations in signalling cascades, including PI3K/AKT, Wnt/β-catenin, and NF-κB. Beta-carbolines display antioxidant, pro-apoptotic, anti-inflammatory, and anti-metastatic activities, with evidence of direct modulation of oncogenic pathways and tumor microenvironment.

The accumulating evidence highlights beta-carbolines as versatile natural agents with multi-faceted mechanisms against chemical-induced hepatocarcinogenesis. Nonetheless, gaps remain in understanding their pharmacokinetics, bioavailability, and long-term safety. Preclinical data are encouraging, but translational studies and clinical validations are limited, underscoring the need for further research.

Beta-carboline alkaloids hold significant promise as therapeutic candidates for chemical- induced HCC. Addressing challenges related to safety, bioavailability, and clinical applicability can prove to be crucial for their future development.