Liver cancer ranks as the second leading cause of cancer-related deaths globally, which remains a significant public health concern. The development of liver cancer is associated with several signaling pathways, particularly metabolic reprogramming. Protein S-palmitoylation, a type of lipid post-translational modification (PTM), involves the reversible attachment of palmitic acid to a cysteine residue through a thioester bond. This modification is found in a wide range of proteins, including enzymes, cancer promoters, tumor suppressors, and transcription factors. The palmitoylation process is catalyzed by the zinc finger DHHC-type containing (ZDHHC) protein family, while the reverse process, depalmitoylation, is facilitated by palmitoyl-protein thioesterases (PPTs). Dysregulation of palmitoylation has been linked to various cancer hallmark functions, cancer metabolism, and tumor microenvironment regulation. Currently, membrane palmitoylated protein (MPP) and PPT1 have been identified as prognostic markers and potential therapeutic targets in liver cancer. In this review, we summarize recent advances in understanding the effects of palmitoylation on liver cancer development, metastasis, and prognosis prediction, and explore potential therapeutic strategies for managing liver cancer.Copyright © 2025. Published by Elsevier Inc.