{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T02:45:34Z","timestamp":1780368334063,"version":"3.54.1"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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 Garcinia dulcis pulp using integrated metabolomic, in silico, and in vitro approaches. Methods: Xanthophyll-rich extracts from G. dulcis pulp were prepared using microwave-assisted extraction. Phytochemical profiling was performed using UHPLC\u2013ESI\u2013MS\/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, \u03b2-cryptoxanthin, \u03b2-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\u2013STAT, 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 IC50 values of 42.8 \u00b1 3.6 \u00b5g\/mL (HepG2) and 58.4 \u00b1 4.9 \u00b5g\/mL (Huh7), while exhibiting significantly lower toxicity toward normal hepatocytes. Conclusions: Xanthophyll-rich extracts from Garcinia dulcis 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 G. dulcis xanthophylls as promising natural candidates for further development in HCC therapy.<\/jats:p>","DOI":"10.3390\/nu18040670","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T15:28:18Z","timestamp":1771428498000},"page":"670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Xanthophyll-Rich Extracts from Garcinia dulcis Pulp as Potential Anti-Hepatocellular Carcinoma Functional Food"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3885-8398","authenticated-orcid":false,"given":"Ulfa","family":"Kholili","sequence":"first","affiliation":[{"name":"Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"},{"name":"Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"},{"name":"Division of Gastroentero-Hepatology, Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aji Bayu","family":"Wicaksono","sequence":"additional","affiliation":[{"name":"Internal Medicine Speciality Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60115, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9384-2172","authenticated-orcid":false,"given":"Amal Arifi","family":"Hidayat","sequence":"additional","affiliation":[{"name":"Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"},{"name":"Division of Gastroentero-Hepatology, Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia"},{"name":"Helicobacter Pylori and Microbiota Study Group, Institute Tropical Disease, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugroseno Yudho","family":"Bintoro","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology Hematology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soetjipto","family":"Soetjipto","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9383-6354","authenticated-orcid":false,"given":"Aryati","family":"Aryati","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1624-0411","authenticated-orcid":false,"given":"Muhammad Zulfikar Fiko","family":"Defianto","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1415-6033","authenticated-orcid":false,"given":"Muhammad","family":"Miftahussurur","sequence":"additional","affiliation":[{"name":"Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya 60132, Indonesia"},{"name":"Division of Gastroentero-Hepatology, Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia"},{"name":"Helicobacter Pylori and Microbiota Study Group, Institute Tropical Disease, Universitas Airlangga, Surabaya 60132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.jhep.2024.10.031","article-title":"Liver Cancer in 2021: Global Burden of Disease Study","volume":"82","author":"Tan","year":"2024","journal-title":"J. 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