Regulated Cell Death in Lenvatinib Resistance of Hepatocellular Carcinoma: from Molecular Mechanisms to Therapeutic Strategies

Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), has been established as the first-line treatment for advanced hepatocellular carcinoma (HCC) because of its superior efficacy when in comparison with sorafenib. However, the inevitable development of drug resistance is a significant barrier to achieve a curative outcome and negatively impacts the prognosis. Therefore, it is imperative to delve into the mechanisms underlying lenvatinib resistance (LR) and to identify potential strategies for rational combination treatments. Regulated cell death (RCD) refers to the process by which cells undergo demise when the adaptive responses are insufficient to maintain homeostasis, and RCD takes a crucial part in the disease progression and response to therapeutic agents including TKI of cancer. Resisting cell death is one of the fundamental hallmarks and the major reasons contributing to drug resistance in cancer. Particularly, numerous studies have demonstrated that RCD (including apoptosis, autophagy, ferroptosis, cuproptosis and pyroptosis) plays a significant role in the emergence of LR in HCC. This article offers an in-depth review of recent discoveries concerning the mechanisms of LR in relation to RCD and proposes potential strategies to boost the effectiveness of lenvatinib by incorporating RCD modulators.