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Plant-derived secondary metabolites represent a promising class of bioactive compounds with structural diversity, multitarget activity, anti-inflammatory effects, and favorable toxicity profiles. This review follows a semi-systematic narrative that synthesizes preclinical and experimental evidence on the anti-inflammatory and anticancer properties of key phytochemicals, including epigallocatechin-3-gallate, galangin, resveratrol, quercetin, curcumin, berberine, genistein, and thymoquinone. These compounds consistently modulate critical inflammation-driven signaling pathways, PI3K\/AKT\/mTOR, NF-\u03baB, JAK\/STAT, Wnt\/\u03b2-catenin, and MAPK, resulting in apoptosis induction, cell cycle arrest, inhibition of angiogenesis, and reduced invasion and metastasis in multiple HCC models. Despite strong preclinical evidence, clinical translation remains limited by variable bioavailability, incomplete safety data, and insufficient human studies. A staged development strategy is recommended: standardized formulations, Good Laboratory Practice-compliant pharmacokinetic\/toxicology studies, validation in patient-derived models, and early-phase, biomarker-guided clinical trials with combination therapy arms. Addressing regulatory, manufacturing, and quality control considerations will be essential for advancing these compounds as adjuvant or complementary agents in precision HCC therapy.<\/jats:p>","DOI":"10.3390\/cimb48020172","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T09:00:58Z","timestamp":1770109258000},"page":"172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Plant-Derived Secondary Metabolites Modulating Inflammation-Driven Pathways in Hepatocellular Carcinoma: Preclinical Insights"],"prefix":"10.3390","volume":"48","author":[{"given":"Sergio Arael","family":"Mendoza-Calder\u00f3n","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n Facultad de Medicina UNAM-UABJO, Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4092-6008","authenticated-orcid":false,"given":"Holanda Isabel","family":"Cruz Luis","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Facultad de Medicina UNAM-UABJO, Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, Mexico"},{"name":"Divisi\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Tecnol\u00f3gico Nacional de M\u00e9xico\/IT Oaxaca, Oaxaca de Ju\u00e1rez 68030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4140-4661","authenticated-orcid":false,"given":"Laura","family":"P\u00e9rez-Campos Mayoral","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Facultad de Medicina UNAM-UABJO, Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, 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