CNDP2, also known as carnosine dipeptidase II, is an enzyme with multiple functions. It is involved in lactate clearance, carnosine hydrolysis, oxidative stress regulation, and metabolite regulation [1]. CNDP2 is crucial in synthesizing Lac-Phe from lactate and phenylalanine in CNDP2+ cells like macrophages, monocytes, immune and epithelial cells, and also in the enzymatic conjugation of β-hydroxybutyrate (BHB) and free amino acids to generate anti-obesity ketone metabolites [2,3,7].

Genetic ablation of CNDP2 in mice has provided insights into its functions. In diet-induced obese mice, CNDP2-mediated Lac-Phe production reduces food intake, adiposity, and body weight, while CNDP2-KO mice have increased food intake and obesity after exercise training [2]. In another study, CNDP2-KO mice had increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet, as the BHB-amino acid production was affected [3,7]. In the context of ferroptosis, CNDP2 KO mice showed aggravated hepatic and renal damage after an acetaminophen overdose, indicating its role in protecting cells under cysteine insufficiency [4]. In cancer research, in ovarian cancer, knockdown of CNDP2 in SKOV3 cells reduced tumor growth in nude mice, while in gastric cancer, over-expression of CNDP2 in cells led to inhibition of cell proliferation and tumor growth in nude mice [5,6].

In conclusion, CNDP2 plays essential roles in metabolism, including energy balance regulation, and in protecting cells from oxidative stress. Its functions are also implicated in various diseases such as obesity-related metabolic disorders, ferroptosis-associated organ damage, and cancer. The use of CNDP2 KO mouse models has significantly enhanced our understanding of these disease-related mechanisms, providing potential directions for therapeutic interventions.