Zdhhc21, zinc finger DHHC domain-containing protein-21, is a palmitoyl acyltransferase. Palmitoylation, the reversible addition of palmitate to cysteine, can alter protein localization, stability, and function, and Zdhhc21 is involved in numerous protein palmitoylation processes. It is associated with various biological pathways and is of great biological importance in processes like oxidative phosphorylation, lipid metabolism, and cell signaling [1,4]. Genetic models such as KO/CKO mouse models are valuable for studying its functions.

In acute myeloid leukemia (AML), Zdhhc21 depletion/inhibition effectively induced myeloid differentiation and weakened stemness potential by inhibiting oxidative phosphorylation. Mechanistically, Zdhhc21 specifically catalyzed the palmitoylation of mitochondrial adenylate kinase 2 (AK2) and further activated oxidative phosphorylation in leukemic blasts [1].

In a FAD pedigree, a Zdhcc21T209S/T209S knock-in mouse model showed cognitive impairment and synaptic dysfunction. The Zdhcc21 p.T209S mutation enhanced FYN palmitoylation, leading to overactivation of NMDAR2B, synaptic dysfunction, and neuronal loss. Palmitoylation of APP was also increased, possibly contributing to Aβ production [2].

In mice with genetic interruption of Zdhhc21, there was attenuated villus structure disorganization associated with thermal injury-induced intestinal barrier damage, suggesting Zdhhc21's role in mediating gut hyperpermeability from thermal injury [3].

In Zdhhc21 functional deficient (Zdhhc21dep/dep) mice, septic injury-induced renal dysfunction was attenuated, with better-preserved renal perfusion and oxygen saturation, and reduced constriction response of renal arteries to α1-adrenergic receptor agonist [5].

In conclusion, Zdhhc21 is crucial in various biological processes through its role in protein palmitoylation. Model-based research, especially using KO/CKO mouse models, has revealed its significance in diseases such as AML, Alzheimer's disease, burn-induced gut epithelial barrier dysfunction, and septic injury-induced renal dysfunction. These findings provide potential therapeutic targets for these disease areas.