The functional roles and therapeutic potential of protein palmitoylation in hepatocellular carcinoma

OBJECTIVE: Protein palmitoylation is a reversible lipid post-translational modification that influences protein stability, membrane association, and signal transduction. Increasing evidence indicates that dysregulated palmitoylation contributes to tumor development by altering the activity of oncogenes, tumor suppressors, transcription factors, and membrane proteins, as well as by reshaping the tumor microenvironment. However, the biological significance of this modification in hepatocellular carcinoma (HCC) has not yet been fully clarified. This review summarizes current knowledge of palmitoylation-mediated regulation in HCC and evaluates its potential as a therapeutic target. METHODS: Relevant studies were identified through systematic searches of PubMed and Web of Science using keywords including "protein palmitoylation," "post-translational modification," "hepatocellular carcinoma," and "tumor therapy." Published evidence was analyzed to examine the roles of palmitoylation in HCC cell proliferation, apoptosis, migration, invasion, and associated signaling pathways. RESULTS: Accumulating evidence indicates that protein palmitoylation contributes to hepatocellular carcinoma progression by modulating the activity and localization of key signaling proteins, including Ras, AKT, and YAP. Through these regulatory effects, palmitoylation influences multiple oncogenic pathways such as Wnt/β-catenin, PI3K/AKT/mTOR, Hippo/YAP, and STAT3 signaling. In addition, metabolic regulatory circuits, including the FASN-ZDHHC-20 and PHF2-SREBP1c axes, link lipid metabolism with palmitoylation-dependent signaling in HCC. Emerging pharmacological approaches targeting palmitoylation-related enzymes-such as palmitoyltransferases and depalmitoylases-have shown promising antitumor activity in preclinical studies. CONCLUSION: Protein palmitoylation represents an important regulatory layer in hepatocellular carcinoma biology, integrating lipid metabolism with oncogenic signaling networks. Therapeutic strategies targeting enzymes that control palmitoylation dynamics may therefore offer new opportunities for HCC treatment. Future investigations should focus on defining the substrate specificity and regulatory mechanisms of individual ZDHHC enzymes, PATs, and depalmitoylases to facilitate the development of more selective therapeutic interventions.