Therapeutic Potential of Quercetin in Hepatocellular Carcinoma: Mechanisms, Challenges, and Clinical Insights

Liver cancer remains a leading cause of cancer-related mortality worldwide, with limited therapeutic efficacy from conventional treatments. Despite advances in chemotherapy and immunotherapy, challenges, including drug resistance and severe adverse effects, persist. Quercetin (Que), a naturally occurring flavonoid, has emerged as a promising therapeutic candidate due to its multitargeted anticancer mechanisms. Que exhibits potent antioxidant, anti-inflammatory, and pro-apoptotic effects by modulating key signaling pathways, including PI3K/Akt/mTOR, JAK/STAT, NF-κB, and MAPK. It inhibits proliferation, induces apoptosis, and suppresses metastasis in hepatocellular carcinoma cell lines by upregulating tumor suppressors (p53, p21) and downregulating oncogenic proteins (cyclin D1, Bcl-2). Additionally, quercetin reverses glycolytic metabolism in cancer cells, enhancing chemosensitivity. Preclinical studies demonstrate that Que reduces tumor growth in xenograft models, supporting its potential as an adjunctive therapy. However, clinical translation faces significant hurdles, including poor bioavailability (approximately 2%), biphasic dose-response effects (antioxidant at low doses versus pro-oxidant at high doses), and inter-individual metabolic variability. Advanced delivery systems, particularly nanoparticle formulations, are being explored to enhance therapeutic efficacy. Recent clinical evidence from randomized controlled trials demonstrates promising hepatoprotective effects, including reduced hepatic fat deposition and potential antiviral activity in patients with liver disease. This review comprehensively examines quercetin's versatile role as a natural therapeutic agent in hepatocellular carcinoma, emphasizing its ability to modulate key signaling pathways, induce apoptosis, and enhance chemosensitivity. Further research is needed to optimize dosing regimens, evaluate long-term safety, and assess synergistic effects with conventional therapies to fully harness quercetin's therapeutic potential in the treatment of hepatocellular carcinoma (HCC). • Liver cancer is the 3rd deadliest malignancy with poor prognosis and treatment. • Quercetin targets PI3K/Akt, MAPK, NF-κB, and Jak/STAT pathways in HCC cells. • It induces cell cycle arrest, autophagy, and inhibits angiogenesis in liver cancer. • Quercetin enhances chemosensitivity and reduces drug resistance in HCC models. • Poor bioavailability limits its therapeutic use; strategies are needed to enhance efficacy.