Ubiquitination in hepatocellular carcinoma: mechanisms and therapeutic opportunities

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, characterized by high malignancy and insidious onset. The majority of patients are diagnosed at intermediate or advanced stages, thereby missing the optimal window for curative treatment. Currently, the combination of targeted agents and immune checkpoint inhibitors (ICIs) represents the standard first-line therapeutic. Nevertheless, the progressive emergence of drug tolerance has become a major clinical concern, highlighting the urgent need for novel targeted therapeutics. Accumulating evidence indicates that dysregulation of the ubiquitination machinery and deubiquitinating enzymes represents a hallmark feature across multiple cancer types. In HCC, the UPS not only orchestrates the degradation of substrate proteins but also modulates the metabolic reprogramming, immune evasion and therapeutic resistance, thereby promoting the proliferation, invasion, and metastasis of HCC cells.This work systematically delineates the roles and molecular mechanisms of ubiquitination in HCC, evaluates its therapeutic potential, and aims to provide a theoretical foundation and critical insights for the development of novel and effective treatment strategies against HCC.