Post-translational modification in hepatocellular carcinoma resistance: molecular mechanisms and therapeutic targeting

Abstract

Hepatocellular carcinoma (HCC), a malignancy with high global morbidity and mortality, has therapeutic resistance as a major focus of both clinical and basic research. In recent years, protein post-translational modifications (PTMs), key regulators of intracellular protein function and cell signaling, play critical roles in therapeutic resistance in liver cancer. Current studies indicate that diverse PTMs—including phosphorylation, ubiquitination, acetylation, lactylation, and glycosylation—modulate liver cancer cell responses to chemotherapy, targeted therapy, immunotherapy and local therapies. This review systematically summarizes the molecular mechanisms and common pathways through which PTMs contribute to therapeutic resistance in liver cancer, explores PTM-mediated mechanism underlying tumor persistence and distant recurrence,examines how PTM-targeted strategies may reverse resistance, and discusses the challenges and prospects of these therapeutic approaches in clinical practice. By integrating current research, this review aims to provide a theoretical basis and potential targets for precision therapy of drug-resistant liver cancer, offering novel intervention targets and translational strategies to overcome therapeutic resistance in HCC.