Naprt, nicotinate phosphoribosyl transferase, is a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis. It catalyzes the first step in the biosynthesis of NAD from nicotinic acid. By regulating intracellular NAD levels, it is involved in the control of the activity of NAD-dependent enzymes, such as sirtuins, PARPs, and NADases, and thus impacts cellular metabolism, inflammation, and signaling [2,3].

In FH-deficient renal cell carcinoma, hypermethylation of the Naprt promoter leads to its silencing, which confers therapeutic vulnerabilities. FH-deficient RCC models with Naprt silencing are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTi), and there is also synergistic tumor cell killing with PARP inhibitors and NAMPTis [1]. In esophageal precancerous lesions, Naprt, rather than NAMPT, is responsible for the stress of excess NAD synthesis, suggesting that developing Naprt inhibitors may prevent and control ESCC [4]. High expression of Naprt in colorectal cancer is associated with vascular invasion, invasion depth, advanced TNM stage, and predicts short overall and disease-free survival time [5]. In glioma, PPM1D mutations drive hypermethylation and epigenetic silencing of Naprt, making PPM1D mutant cells sensitive to NAMPT inhibitors [6].

In conclusion, Naprt is crucial for NAD+ biosynthesis and has far-reaching effects on multiple biological processes and disease conditions. Studies using genetic models, though not specifically KO/CKO mouse models in the provided references, have revealed its significance in cancers like renal cell carcinoma, esophageal cancer, colorectal cancer, and glioma, highlighting its potential as a therapeutic target in these disease areas.