<p>Liver cancer (LC) stands as one of the most prevalent and highly malignant tumors globally, with persistently elevated mortality rates. For advanced-stage LC, identifying efficacious treatment modalities remains a critical imperative. Cuproptosis, a newly identified form of regulated cell death, exhibits therapeutic potential for impeding LC progression. However, the current clinical evidence remains limited, meriting further in-depth investigation by researchers. Existing literature has summarized copper homeostasis, the molecular mechanisms of cuproptosis, and its roles in certain cancers. However, key challenges in clinical translation haven’t been included in the research scope, such as the mechanistic complexity, poor targeting specificity, lack of mature biomarkers, and risk of therapeutic resistance. Notably, the lessons from failed clinical trials have not been fully integrated into ongoing investigations. This review systematically delineates cuproptosis-associated biomarkers in LC, critically analyzes the challenges of targeting cuproptosis for LC therapy and discusses potential solutions. By highlighting current research gaps, we aim to provide actionable research directions for future investigations.</p>