Therapeutic potential and molecular mechanisms of citrus flavonoids in hepatocellular carcinoma

Citrus-derived flavonoids, particularly naringenin, hesperidin, and hesperetin, have emerged as promising bioactive compounds with potential therapeutic relevance in hepatocellular carcinoma (HCC). This review provides a focused synthesis of current preclinical evidence regarding their anticancer properties and underlying molecular mechanisms in experimental HCC models. These flavonoids exert broad anticancer effects, including inhibition of cell proliferation, induction of apoptosis, reduction of oxidative stress, and suppression of tumor progression and metastasis. These activities are mediated through modulation of key oncogenic signaling pathways, which are critically involved in hepatocarcinogenesis. In addition, citrus flavonoids influence mitochondrial function and cellular redox homeostasis, thereby contributing to programmed cell death and metabolic regulation. Preclinical studies further indicate that these compounds may enhance the efficacy of conventional chemotherapeutic agents, including cisplatin, doxorubicin, and sorafenib, while exhibiting reduced toxicity toward normal cells. Moreover, nanoformulation-based delivery systems have been shown to improve their bioavailability and therapeutic performance in experimental models. In vivo evidence supports their hepatoprotective effects, with reductions in tumor burden and attenuation of inflammation and fibrosis. Collectively, citrus flavonoids represent promising adjunctive candidates for HCC therapy; however, clinical validation remains limited, and further translational studies are required to confirm their therapeutic applicability in humans.