Deubiquitinating Enzymes as Therapeutic Candidates in Hepatocellular Carcinoma and Other Liver Disease

Hepatocellular carcinoma is challenging to detect at an early stage, and its severity increases over time. Recently, the incidence of hepatocellular carcinoma has increased, partly due to lifestyle-related factors such as excessive alcohol intake, sedentary behavior, and diets high in fat, which contribute to the growing prevalence of fatty liver and hepatitis. Various therapeutic strategies are being explored for hepatocellular carcinoma, among which therapies targeting deubiquitinating enzymes (DUBs) have attracted growing attention. Ubiquitination acts as a crucial modulator in the regulation of intracellular signaling across many diseases. E3 ligase recognizes the target protein and transfers ubiquitin, received from the E2 enzyme, to the lysine residues of the substrate, thereby conferring specificity to the ubiquitination process. Once a ubiquitin chain is attached to a target protein by an E3 ligase, the protein is directed to the ubiquitin–proteasome system (UPS) for degradation. In this process, the 26S proteasome complex recognizes the ubiquitin chain and degrades the target protein, thereby serving as a major mechanism for maintaining protein homeostasis. Through this pathway, cells regulate signal transduction, eliminate abnormal proteins, and perform various essential functions. On the other hand, deubiquitinating enzymes (DUBs) recognize the ubiquitin chains on target proteins and remove them by hydrolyzing the isopeptide bonds of ubiquitin, thereby enabling the target proteins to evade degradation by the proteasome system. Furthermore, deubiquitinating enzymes independently remove ubiquitin from proteins and can serve as central regulators in signaling pathways related to hepatocellular carcinoma.