Protein lipidation is a critical post-translational modification that enhances protein hydrophobicity, influencing protein trafficking, localization, stability, conformation, interactions, and signal transduction. Five main types of protein lipidations include S-palmitoylation, N-myristoylation, S-prenylation, GPI anchor, and cholesterylation. These modifications are essential for various physiological functions and are closely linked to diseases. Research has shown that targeting protein lipidation is a promising therapeutic strategy, with several drugs, such as asciminib and lonafarnib, already approved for clinical use. S-palmitoylation is catalyzed by DHHC-PATs, which modify cysteine residues on proteins. The process involves autopalmitoylation and subsequent transfer of palmitate to the substrate. DHHC-PATs are localized in various cellular compartments and play roles in protein trafficking and localization. However, the exact mechanisms of S-palmitoylation remain unclear, and the development of specific inhibitors is needed for further research. Depalmitoylation is mediated by enzymes such as APTs, PPTs, and ABHDs, which cleave the thioester bond on palmitoylated proteins. These enzymes are crucial for regulating protein stability and degradation. For example, APT1 and APT2 are involved in the depalmitoylation of various proteins, including PD-L1, which is important in immune checkpoint therapy. S-palmitoylation also plays a role in protein conformation and interaction, affecting protein function and signaling pathways. It influences the stability and degradation of proteins, with some proteins being protected from lysosomal degradation by S-palmitoylation. Additionally, S-palmitoylation is involved in signal transduction pathways, including those related to cancer, immune responses, and cell proliferation. In cancer, S-palmitoylation is strongly associated with tumour progression and resistance to therapy. Dysregulation of S-palmitoylation can lead to abnormal protein trafficking and activation of oncogenic pathways. However, S-palmitoylation can also act as a tumour suppressor by activating tumour suppressor signals or blocking oncogene signals. For example, S-palmitoylation of the melanocortin-1 receptor (MC1R) can protect against melanoma by enhancing its signaling. Overall, protein lipidation is a complex and dynamic process that plays a crucial role in various physiological functions and disease pathogenesis. Understanding the mechanisms of protein lipidation and developing targeted therapies could lead to new treatments for a wide range of diseases.Protein lipidation is a critical post-translational modification that enhances protein hydrophobicity, influencing protein trafficking, localization, stability, conformation, interactions, and signal transduction. Five main types of protein lipidations include S-palmitoylation, N-myristoylation, S-prenylation, GPI anchor, and cholesterylation. These modifications are essential for various physiological functions and are closely linked to diseases. Research has shown that targeting protein lipidation is a promising therapeutic strategy, with several drugs, such as asciminib and lonafarnib, already approved for clinical use. S-palmitoylation is catalyzed by DHHC-PATs, which modify cysteine residues on proteins. The process involves autopalmitoylation and subsequent transfer of palmitate to the substrate. DHHC-PATs are localized in various cellular compartments and play roles in protein trafficking and localization. However, the exact mechanisms of S-palmitoylation remain unclear, and the development of specific inhibitors is needed for further research. Depalmitoylation is mediated by enzymes such as APTs, PPTs, and ABHDs, which cleave the thioester bond on palmitoylated proteins. These enzymes are crucial for regulating protein stability and degradation. For example, APT1 and APT2 are involved in the depalmitoylation of various proteins, including PD-L1, which is important in immune checkpoint therapy. S-palmitoylation also plays a role in protein conformation and interaction, affecting protein function and signaling pathways. It influences the stability and degradation of proteins, with some proteins being protected from lysosomal degradation by S-palmitoylation. Additionally, S-palmitoylation is involved in signal transduction pathways, including those related to cancer, immune responses, and cell proliferation. In cancer, S-palmitoylation is strongly associated with tumour progression and resistance to therapy. Dysregulation of S-palmitoylation can lead to abnormal protein trafficking and activation of oncogenic pathways. However, S-palmitoylation can also act as a tumour suppressor by activating tumour suppressor signals or blocking oncogene signals. For example, S-palmitoylation of the melanocortin-1 receptor (MC1R) can protect against melanoma by enhancing its signaling. Overall, protein lipidation is a complex and dynamic process that plays a crucial role in various physiological functions and disease pathogenesis. Understanding the mechanisms of protein lipidation and developing targeted therapies could lead to new treatments for a wide range of diseases.