Recent Advances in Kinase Targeting for Hepatocellular Carcinoma: Emerging Strategies and Clinical Insights

Liver cancer currently stands as the leading cause of cancer-related mortality worldwide, with Hepatocellular Carcinoma (HCC) accounting for approximately 90% of all cases, making it the most prevalent and clinically significant form of primary liver cancer. First-line treatments typically include sorafenib, lenvatinib, or immunotherapies such as immune checkpoint inhibitors. However, drug resistance and treatment-associated toxicities have significantly limited the overall effectiveness of these therapeutic approaches, contributing to persistently high mortality rates despite medical advances. Unfortunately, alternative interventions such as transarterial chemoembolization and ablation are often not feasible due to the advanced stage at which the disease is usually diagnosed, thereby restricting the applicability of localized or surgical approaches with curative potential. Recent literature has increasingly highlighted the urgent need to develop innovative therapeutic strategies that focus on targeting alternative signaling pathways and exploring novel drug candidates capable of overcoming well-established resistance mechanisms. In this context, our study presents a comprehensive analysis of key kinase targets associated with HCC that have been under clinical investigation over the past decade, emphasizing molecular mechanisms involved in tumor progression, angiogenesis, metabolic dysregulation, and immune evasion. Our findings indicate promising advances, particularly in the development of next-generation multikinase inhibitors and in combining targeted therapies with immunotherapy, which have already demonstrated the potential to significantly improve clinical responses, extend survival outcomes, and reduce adverse effects. These findings underscore the importance of adopting personalized, tumor biology-based strategies and highlight a clear perspective that kinase-targeted therapies represent a promising direction for the future of HCC treatment.