Protein acylation, a common form of saturated or unsaturated lipid modification, has been found occurring on thousands of proteins, peptides and endogenous molecules and regulating numerous pathways. Among these events, palmitoylation specifically represents palmitic (C16) modification, in mammals and can be divided into three different forms depending on the binding sites, which is responsible for the covalent binding of palmitoyl [1]. N-palmitoylation is the attachment of a palmitoyl group to the amino group of glycine, lysine or cysteine residues through stable amide bonds [2,3]. O-palmitoylation takes place in the serine residues through ester bonds [4]. S-palmitoylation is the covalent binding of palmitoyl group to cysteine residues, which is the only reversible form due to the instability of thioester bonds [5]. S-palmitoylation is divided into substrate self-palmitoylation and protein acyltransferase (PAT)-catalyzed substrate palmitoylation [6]. S-palmitoylation catalyzed by PAT is divided into two processes. The first step is the acylation of cysteine residues in the DHHC motif of the enzyme by palmitoyl-CoA (Palm-CoA) to form acyl intermediates. This step is often referred as self-palmitoylation of the enzyme. The second step is the partial transfer of the palmitoyl group to the specific cysteine residue in the protein substrate [7]. So far, it has been found that palmitoylation modification not only influences structure stability, assembly and maturation of various proteins, but also regulates their translocation and cellular localization [[8], [9], [10]], which in turn affects many physiological processes such as signal transduction and cell adhesion [11].

Moreover, it has been found that some small peptides and endogenous molecules can also be palmitoylated to maintain normal physiological functions or generate functional molecules. This process can be primarily categorized into two types: enzyme-mediated and non-enzyme-mediated palmitoylation. The first type is primarily catalyzed by carnitine palmitoyltransferase (CPT), serine palmitoyltransferase (SPT) or Ghrelin O-acyltransferase (GOAT), while the non-enzymatic palmitoylation involves some synthetic peptides, which are crucial for preserving the normal physiological functions of living organisms [[12], [13], [14]].

Numerous studies have demonstrated that regulating the palmitoylation process affect a variety of diseases, such as neurological diseases (Alzheimer's disease) and cancer (stomach cancer, lung cancer, etc.) [15,16]. These results indicate the great potential of palmitoylation modulators. Herein we introduce the proteins and small molecules that can undergo palmitoylation. Importantly, the available broad-spectrum and selective inhibitors for related enzymes that catalyze these processes are highlighted and structure-function relationships (SAR) were discussed.