Zdhhc4, also known as zinc finger DHHC domain-containing palmitoyltransferase 4, is an enzyme that catalyzes S-palmitoylation, a post-translational modification. Palmitoylation is crucial for various biological processes, such as protein trafficking, membrane localization, and signal transduction [1-10]. It is involved in multiple pathways related to immunity, pain sensation, tumorigenesis, and metabolism [1-7]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable in studying Zdhhc4 function.

In tumor-related studies, GSK3β palmitoylation mediated by Zdhhc4 at the Cys14 residue enhanced temozolomide resistance and self-renewal of glioblastoma stem cells, activating the EZH2-STAT3 pathway [2]. In diabetes research, the FoxO1-Zdhhc4-CD36 S-acylation axis drives metabolic and contractile dysfunction in the type 2 diabetic heart, as Zdhhc4 transcriptionally upregulates in the diabetic heart and its genetic silencing decreases CD36 S-acylation [3]. In pain research, Zdhhc4-mediated palmitoylation of TRPV1 at specific cysteine residues promotes its degradation via the lysosome pathway, facilitating inflammatory pain relief [1].

In conclusion, Zdhhc4 plays essential roles in multiple biological processes through its palmitoylation function. Model-based research, especially KO/CKO mouse models, has contributed to understanding its role in diseases such as glioblastoma and diabetes, as well as in pain-related biological processes. This knowledge provides insights into the underlying mechanisms of these diseases and potential therapeutic targets.