Dietary polyphenols and hepatocellular carcinoma: protective mechanisms, challenges, and future directions

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with pathogenesis driven by metabolic reprogramming, oxidative stress, chronic inflammation, and dysregulation of multiple signaling pathways. Dietary polyphenols-a structurally diverse group of phytochemicals abundant in fruits, vegetables, tea, and medicinal plants-have emerged as promising chemopreventive and therapeutic agents due to their pleiotropic bioactivities. This comprehensive review systematically searched PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar for relevant literature published from 2014 to 2025. It outlines the molecular mechanisms through which dietary polyphenols (including phenolic acids, flavonoids, lignans, stilbenes, and others) suppress HCC development by modulating lipid metabolism, glucose homeostasis, mitochondrial function, oxidative stress, inflammatory responses, and detoxification pathways. Special emphasis is placed on their ability to reshape the tumor microenvironment (TME) and their synergistic potential when combined with conventional treatments. Nevertheless, the clinical translation of polyphenols is hampered by limitations such as poor bioavailability, chemical instability, and insufficient clinical validation. Future efforts should prioritize the development of advanced delivery systems (e.g., nanoformulations), investigation of polyphenol-drug synergies, and validation through rigorously designed clinical trials. This review underscores the promise of dietary polyphenols as complementary agents for HCC prevention and treatment, while highlighting the imperative for further mechanistic and translational research.