Zdhhc5, a member of the palmitoyl-acyltransferase (PAT) family, is mainly localized to the plasma membrane and contains an extended cytoplasmic domain. It plays a vital role in protein palmitoylation, a process crucial for a range of cellular processes such as synaptic plasticity, cardiac function, cell adhesion, and fatty acid uptake [4]. Protein palmitoylation mediated by Zdhhc5 is involved in multiple pathways, including those related to innate immune response, lipid metabolism, and cancer-related processes.

Zdhhc5-/-mice showed defective NLRP3 inflammasome activation in vivo. Silencing Zdhhc5 blocked NLRP3 oligomerization, NLRP3-NEK7 interaction, and formation of large intracellular ASC aggregates, leading to abrogation of caspase-1 activation, IL-1β/18 release, and GSDMD cleavage, both in human cells and in mice [1]. In the context of fatty liver disease, hypothalamic microglia-specific PKCδ knockdown, which is related to Zdhhc5-mediated palmitoylation, markedly impaired artemether-dependent neuroendocrine regulation and lipid metabolism improvement in mice [2]. In glioma, knockdown of Zdhhc5 abrogated the S-palmitoylation and membrane distribution of FAK, and impaired cell proliferation, invasion, and epithelial-mesenchymal transition [3].

In conclusion, Zdhhc5 is essential for protein palmitoylation and is involved in key biological processes. Studies using Zdhhc5 knockout or knockdown models have revealed its significance in diseases such as NLRP3 inflammasome-driven diseases, fatty liver disease, and glioma. These models have provided valuable insights into the role of Zdhhc5 in specific disease-related pathways, which may offer potential therapeutic targets for these diseases.