Natural phenolic compounds as modulators of radiation response in hepatocellular carcinoma

Radiotherapy remains a cornerstone in the treatment of hepatocellular carcinoma (HCC), yet its clinical efficacy is constrained by the intrinsic radioresistance of liver tumors and the dose-limiting toxicity to surrounding healthy tissue. Natural phenolic compounds (NPCs), including flavonoids (apigenin, genistein, quercetin, fisetin, wogonin, isoliquiritigenin, corylin and epigallocatechin gallate) and other classes (ellagic acid, ferulic acid, chlorogenic acid, pterostilbene, resveratrol, magnolol, curcumin, liensinine, emodin, verbascoside and caffeic acid phenethyl ester), have emerged as promising agents to expand this therapeutic window. Evidence suggests that many NPCs enhance radiosensitivity in HCC cells through convergent mechanisms such as disrupting redox homeostasis to impair Nrf2-mediated antioxidant defenses, inhibiting DNA repair pathways, and reversing hypoxia-driven metabolic reprogramming. Nevertheless, radiosensitizing effects of NPCs is context-dependent, for instance, resveratrol (under hypoxic condition) and chlorogenic acid have demonstrated radioprotective properties, potentially counteracting therapeutic goals. Additionally, methodological limitations-including the use of misidentified cell lines-raise concerns about the reliability of the reported safety and selectivity outcomes for NPCs. Translational success will hinge on overcoming challenges such as poor bioavailability, which may be addressed through tumor-microenvironment-responsive nanotechnology, and exploring synergistic strategies that combine NPCs with radiotherapy and immunotherapy. While NPCs hold considerable promise as radiosensitizers for HCC, future progress requires rigorous validation in authentic adult HCC models to ensure clinical relevance and efficacy.