Xanthophyll-Rich Extracts from Pulp as Potential Anti-Hepatocellular Carcinoma Functional Food.

[INTRODUCTION] Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and remains a leading cause of cancer-related mortality worldwide. Despite recent advances in immunotherapy and targeted agents, treatment efficacy is frequently limited by tumor heterogeneity, drug resistance, and systemic toxicity. Natural products, particularly carotenoid-derived compounds, have emerged as promising multi-target anticancer agents. Xanthophylls, a class of oxygenated carotenoids, exhibit pleiotropic biological activities that are relevant to cancer therapy; however, their potential against HCC remains incompletely explored. This study aimed to systematically evaluate the anti-HCC potential of xanthophyll-rich extracts from pulp using integrated metabolomic, in silico, and in vitro approaches.

[METHODS] Xanthophyll-rich extracts from pulp were prepared using microwave-assisted extraction. Phytochemical profiling was performed using UHPLC-ESI-MS/MS. In silico analyses included bioactivity prediction, ADMET profiling, target identification, network pharmacology, pathway enrichment, and molecular docking against key HCC-related proteins (EGFR, BCL-2, and mTOR). In vitro antiproliferative activity was assessed using MTT assays on HepG2 and Huh7 hepatocellular carcinoma cell lines, with THLE-2 normal hepatocytes used as controls.

[RESULTS] Metabolomic analysis revealed a xanthophyll-dominated profile, with zeaxanthin and lutein as the major constituents, alongside fucoxanthin, astaxanthin, β-cryptoxanthin, β-carotene, and canthaxanthin. In silico predictions demonstrated high antineoplastic and pro-apoptotic activities, with strong involvement in the HIF-1, EGFR, PD-1/PD-L1, JAK-STAT, and mTOR signaling pathways. Molecular docking confirmed stable and high-affinity interactions of xanthophylls with EGFR, BCL-2, and mTOR. In vitro assays showed selective cytotoxicity against HCC cells, with IC values of 42.8 ± 3.6 µg/mL (HepG2) and 58.4 ± 4.9 µg/mL (Huh7), while exhibiting significantly lower toxicity toward normal hepatocytes.

[CONCLUSIONS] Xanthophyll-rich extracts from pulp exhibit potent and selective anti-hepatocellular carcinoma activity through multi-target mechanisms involving oncogenic signaling, apoptosis regulation, and tumor metabolism. These findings support the translational potential of xanthophylls as promising natural candidates for further development in HCC therapy.