Treating liver cancer through arginine depletion

•Liver cancer, a global threat, ranks sixth in incidence and is the second-leading cause of cancer fatalities.•Despite effective treatments, issues like affordability and accessibility persist, especially in developing nations.•Researchers shift focus to cancer cell metabolism for safer and more effective alternatives, highlighting arginine depletion approaches.•Fused recombinant human arginase 1 variants emerge as a effective, affordable, and safe solution for combating liver cancer globally. Liver cancer, the sixth most common cancer globally and the second-leading cause of cancer-related deaths, presents a critical public health threat. Diagnosis often occurs in advanced stages of the disease, aligning incidence with fatality rates. Given that established treatments, such as stereotactic body radiation therapy and transarterial radioembolization, face accessibility and affordability challenges, the emerging focus on cancer cell metabolism, particularly arginine (Arg) depletion, offers a promising research avenue. Arg-depleting enzymes show efficacy against Arg-auxotrophic cancers, including hepatocellular carcinoma (HCC). Thus, in this review, we explore the limitations of current therapies and highlight the potential of Arg depletion, emphasizing various Arg-hydrolyzing enzymes in clinical development.