Resistance of first-line targeted drugs in hepatocellular carcinoma: the epigenetic regulation mechanisms

Targeted therapy has revolutionized the treatment landscape of hepatocellular carcinoma (HCC), offering unprecedented hope to patients. However, despite its promise, significant challenges arise in the form of drug resistance. Only a fraction of HCC patients respond to targeted therapy, and even those who respond often develop resistance over time. Sorafenib and lenvatinib, the sole first-line targeted therapeutic drugs for HCC, face severe clinical limitations due to drug resistance. Understanding the mechanisms underlying sorafenib/lenvatinib resistance is crucial for maximizing treatment efficacy. Recent studies have highlighted the pivotal role of epigenetic regulation in drug resistance. Cancer is recognized as both a genetic and epigenetic disease, with epigenetic factors influencing various aspects of tumor cell biology, especially drug resistance. This review systematically summarizes the mechanisms of epigenetic-mediated sorafenib/lenvatinib resistance, encompassing non-coding RNA (ncRNA) regulation, DNA methylation, RNA methylation, and histone modification. These abnormal epigenetic processes typically influence biological activities, including escaped programmed cell death, tumor metabolic reprogramming, formation and maintenance of drug-resistant cells, uncontrolled cell proliferation signaling pathways, and abnormal transport processes, ultimately culminating in profound drug resistance. By comprehensively summarizing the latest discoveries in epigenetic regulation mechanisms, this review highlights potential strategies to overcome drug resistance, paving the way for future advancements in HCC treatment.