ZDHHC3, Zinc finger DHHC-type palmitoyltransferase 3, is a key enzyme responsible for catalyzing S-palmitoylation, a post-translational lipid modification. Palmitoylation is involved in diverse cellular processes such as protein trafficking, membrane localization, and signal transduction [1,2,3,4,5,6,7,8]. It plays a role in multiple biological pathways and is of great biological importance in various tissues and organisms [1-10]. Genetic models, like KO/CKO mouse models, are valuable tools for studying its functions.

In non-alcoholic steatohepatitis (NASH), hepatocyte-specific dysfunction of ZDHHC3 significantly inhibits palmitoylated IRHOM2 deposition, suppressing fatty-acids-mediated hepatosteatosis and inflammation in vitro and NASH pathological phenotypes in rodent and rabbit models [1]. In hepatocellular carcinoma (HCC), the small-molecule inhibitor of ZDHHC3 combined with anti-PD-1 immunotherapy inhibits DEN/CCl4-induced HCC growth in mice, as ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape [2]. In the central nervous system, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model [3]. In kidney clear cell carcinoma (KIRC), zDHHC3 suppression leads to decreased S-palmitoylation of SLC9A2 and inhibits Caki-2 cell apoptosis [4].

In conclusion, ZDHHC3 is crucial for S-palmitoylation-mediated biological processes. Model-based research, especially KO/CKO mouse models, has revealed its role in diseases like NASH, HCC, CNS demyelination diseases, and KIRC. Understanding ZDHHC3 functions provides insights into disease mechanisms and potential therapeutic targets for these diseases.

References:

1. Xu, Minxuan, Tan, Jun, Zhu, Liancai, Zou, Benkui, Wang, Bochu. 2023. Palmitoyltransferase ZDHHC3 Aggravates Nonalcoholic Steatohepatitis by Targeting S-Palmitoylated IRHOM2. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2302130. doi:10.1002/advs.202302130. https://pubmed.ncbi.nlm.nih.gov/37544908/

2. Wu, Mingzhi, Zhou, Xiaojun, Zhou, Xinyi, Wang, Fubing, Li, Youjun. 2024. ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape in hepatocellular carcinoma. In Cell reports, 43, 114962. doi:10.1016/j.celrep.2024.114962. https://pubmed.ncbi.nlm.nih.gov/39522165/

3. Chang, Yanli, Zhu, Jiangli, Li, Xiaopeng, Wang, Xiaoning, Kong, Eryan. 2024. Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system. In Signal transduction and targeted therapy, 9, 254. doi:10.1038/s41392-024-01971-5. https://pubmed.ncbi.nlm.nih.gov/39327467/

4. Zhang, Xiuyun, Hou, Junpeng, Zhou, Guangyuan, Wang, Haixia, Wu, Zeang. 2024. zDHHC3-mediated S-palmitoylation of SLC9A2 regulates apoptosis in kidney clear cell carcinoma. In Journal of cancer research and clinical oncology, 150, 194. doi:10.1007/s00432-024-05737-y. https://pubmed.ncbi.nlm.nih.gov/38619631/

5. Yao, Han, Lan, Jiang, Li, Chushu, Cui, Yun, Xu, Jie. 2019. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. In Nature biomedical engineering, 3, 306-317. doi:10.1038/s41551-019-0375-6. https://pubmed.ncbi.nlm.nih.gov/30952982/

6. Jing, Huiyuan, Liu, Ying, Song, Yvzhen, Liu, Jie, Zhao, Pandeng. 2025. ZDHHC3-LYPLA1 regulates PRRSV-2 replication through reversible palmitoylation. In Veterinary microbiology, 301, 110368. doi:10.1016/j.vetmic.2025.110368. https://pubmed.ncbi.nlm.nih.gov/39787744/

7. Lievens, Patricia Marie-Jeanne, Kuznetsova, Tatiana, Kochlamazashvili, Gaga, Ponimaskin, Evgeni, Dityatev, Alexander. 2016. ZDHHC3 Tyrosine Phosphorylation Regulates Neural Cell Adhesion Molecule Palmitoylation. In Molecular and cellular biology, 36, 2208-25. doi:10.1128/MCB.00144-16. https://pubmed.ncbi.nlm.nih.gov/27247265/

8. Baldwin, Tanya A, Teuber, James P, Kuwabara, Yasuhide, Brody, Matthew J, Molkentin, Jeffery D. 2023. Palmitoylation-dependent regulation of cardiomyocyte Rac1 signaling activity and minor effects on cardiac hypertrophy. In The Journal of biological chemistry, 299, 105426. doi:10.1016/j.jbc.2023.105426. https://pubmed.ncbi.nlm.nih.gov/37926281/