Nadk, short for nicotinamide adenine dinucleotide (NAD+) kinase, is the sole enzyme that phosphorylates NAD+ to produce nicotinamide adenine dinucleotide phosphate (NADP), a crucial co-factor for lipid and redox homeostasis [1,2,3,4,7]. The NADK genes and the NADP(H)-producing mechanism are evolutionarily conserved among archaea, bacteria, plants, and mammals [1]. NADK is involved in multiple biological processes and has significant pathophysiological importance [1]. Genetic models have been valuable in validating its essential role in cellular redox homeostasis and metabolism in multicellular organisms [1].

In breast cancer, NADK-mediated de novo NADP(H) synthesis is essential for metastasis. Metastatic signals epigenetically up-regulate NADK, expanding the NADP(H) pools and enabling cells to adapt to the metastatic cascade [2]. In pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS promotes PKC-mediated NADK phosphorylation and hyperactivation, sustaining NADP+ and NADPH levels [3]. In the razor clam, ScNADK is involved in proline synthesis under high-salinity stress, enhancing the clam's ability to tolerate salinity variations [4]. In lung adenocarcinoma (LUAD), knockdown of NADK promotes ferroptosis by regulating the NADPH/FSP1 axis, as NADK is over-expressed in LUAD patients [5]. In non-small cell lung carcinoma, NUAK1-mediated phosphorylation of NADK at serine 64 mitigates osimertinib-induced ROS accumulation, leading to osimertinib resistance [6].

In conclusion, Nadk plays essential roles in maintaining cellular redox and metabolic homeostasis. Through model-based research, it has been shown to be involved in various disease conditions such as cancer metastasis, cancer cell survival under stress, and osmoregulation in organisms. The study of Nadk using gene knockout or knockdown models has provided insights into its role in these specific biological processes and disease areas, suggesting it could be a potential therapeutic target for related diseases.