Synergizing tyrosine kinase inhibitors with structurally diverse natural products: strategies to enhance efficacy and overcome drug resistance in liver cancer

Liver cancer is characterized by high global incidence and mortality rates. Multi-target tyrosine kinase inhibitors (TKIs), such as sorafenib, are crucial targeted therapy drugs for treating liver cancer. However, drug resistance limits their effectiveness, and monotherapy accelerates resistance, emphasizing the need for combination therapies. Natural products, due to their structural diversity, have demonstrated potential in delaying drug resistance by modulating various cancer-related pathways. Notably, several natural products have been effectively combined with TKIs, exhibiting synergistic effects in liver cancer treatment and mitigating resistance. Therefore, in this review, we summarize natural products identified over the past decade that have been used in combination with TKIs for liver cancer therapy. Specifically, we systematically summarize their structural characteristics and underlying mechanisms contributing to their synergistic effects in combinational therapy. The integration of natural products with TKIs may enhance current monotherapy strategies, overcome resistance, and improve liver cancer treatment outcomes, offering a promising direction for future therapy.