CNDP2, also known as carnosine dipeptidase II, is an enzyme with multiple essential functions. It catalyzes the formation of Lac-Phe, an exercise-induced metabolite from lactate, and is involved in lactate clearance, carnosine hydrolysis, oxidative stress regulation, and metabolite regulation. It is also associated with cardiometabolic, renal diseases, and has implications in cancer-related pathways such as PI3K/AKT, MAPK, and cooperative nutrient scavenging in the tumor microenvironment [1,4,6,9]. Genetic models, like KO mouse models, are valuable for studying its functions.

In KO mouse models, genetic ablation of CNDP2 eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels, leading to increased food intake and body weight upon ketosis stimuli or exogenous ketone ester supplementation [2,8]. In the context of metformin's action, genetic ablation of CNDP2 in mice renders them resistant to metformin's anorexigenic and anti-obesity effects, establishing the CNDP2/Lac-Phe pathway as a critical mediator of metformin's effects on energy balance [3,7]. Also, CNDP2 KO mice show aggravated hepatic and renal damage upon an acetaminophen overdose, indicating its role in protecting cells under cysteine insufficiency [5].

In conclusion, CNDP2 is a key enzyme in multiple biological processes. Model-based research, especially through KO mouse models, has revealed its role in energy balance, metabolite regulation, and cell protection under stress. In diseases, it is implicated in cardiometabolic, renal conditions, and cancer, highlighting its potential as a therapeutic target.

References:

1. Ocariza, Moizle Grace Castro, Paton, Louise Nancy, Templeton, Evelyn Mary, Pilbrow, Anna Pauline, Appleby, Sarah. 2024. CNDP2: An Enzyme Linking Metabolism and Cardiovascular Diseases? In Journal of cardiovascular translational research, 18, 48-57. doi:10.1007/s12265-024-10560-4. https://pubmed.ncbi.nlm.nih.gov/39349903/

2. Moya-Garzon, Maria Dolores, Wang, Mengjie, Li, Veronica L, Xu, Yong, Long, Jonathan Z. 2024. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. In Cell, 188, 175-186.e20. doi:10.1016/j.cell.2024.10.032. https://pubmed.ncbi.nlm.nih.gov/39536746/

3. Xiao, Shuke, Li, Veronica L, Lyu, Xuchao, Benson, Mark D, Long, Jonathan Z. 2024. Lac-Phe mediates the effects of metformin on food intake and body weight. In Nature metabolism, 6, 659-669. doi:10.1038/s42255-024-00999-9. https://pubmed.ncbi.nlm.nih.gov/38499766/

4. Zhang, Li Q, Yang, Hua Q, Yang, Su Q, Lu, Hong S, Zhao, Ling P. . CNDP2 Acts as an Activator for Human Ovarian Cancer Growth and Metastasis via the PI3K/AKT Pathway. In Technology in cancer research & treatment, 18, 1533033819874773. doi:10.1177/1533033819874773. https://pubmed.ncbi.nlm.nih.gov/31537175/

5. Kobayashi, Sho, Homma, Takujiro, Okumura, Nobuaki, Takao, Toshifumi, Fujii, Junichi. 2021. Carnosine dipeptidase II (CNDP2) protects cells under cysteine insufficiency by hydrolyzing glutathione-related peptides. In Free radical biology & medicine, 174, 12-27. doi:10.1016/j.freeradbiomed.2021.07.036. https://pubmed.ncbi.nlm.nih.gov/34324979/

6. Zhang, Zhenwei, Miao, Lei, Xin, Xiaoming, Kong, Xiangping, Jiao, Binghua. 2014. Underexpressed CNDP2 participates in gastric cancer growth inhibition through activating the MAPK signaling pathway. In Molecular medicine (Cambridge, Mass.), 20, 17-28. doi:10.2119/molmed.2013.00102. https://pubmed.ncbi.nlm.nih.gov/24395568/

7. Xiao, Shuke, Li, Veronica L, Lyu, Xuchao, Benson, Mark D, Long, Jonathan Z. 2023. Lac-Phe mediates the anti-obesity effect of metformin. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.11.02.565321. https://pubmed.ncbi.nlm.nih.gov/37961394/

8. Moya-Garzon, Maria Dolores, Wang, Mengjie, Li, Veronica L, Xu, Yong, Long, Jonathan Z. 2024. A secondary β-hydroxybutyrate metabolic pathway linked to energy balance. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.09.09.612087. https://pubmed.ncbi.nlm.nih.gov/39314488/

9. Guzelsoy, Gizem, Elorza, Setiembre D, Ros, Manon, Papagiannakopoulos, Thales, Carmona-Fontaine, Carlos. 2025. Cooperative nutrient scavenging is an evolutionary advantage in cancer. In Nature, 640, 534-542. doi:10.1038/s41586-025-08588-w. https://pubmed.ncbi.nlm.nih.gov/39972131/