Fxyd2, a regulatory subunit of Na,K-ATPase, also known as the γ subunit, is crucial for adapting the functional properties of Na,K-ATPase to cellular requirements. It is involved in multiple biological processes, such as renal Mg handling, pain regulation, and cell growth, and is associated with various diseases including hypomagnesemia, chronic pain, and glioma [1,2,3]. The study of Fxyd2 through genetic models like KO mouse models can provide valuable insights into its functions.

In KO mouse models, adult Fxyd2 (-∕-) mice exhibited beneficial phenotypes. In the kidney, there was elevated activity of Na,K-ATPase and apical sodium transporters, yet the mice maintained sodium balance and normotensive state. They also showed enhanced glucose tolerance, increased circulating insulin, and no insulin resistance, along with increased beta cell proliferation and mass related to PI3K-Akt pathway activation [5]. In addition, loss of Fxyd2 function, either constitutively in Fxyd2-/- mice or acutely in neuropathic rats, alleviated mechanical hypersensitivity induced by peripheral nerve lesions, indicating its role in maintaining neuropathic pain [4].

In conclusion, Fxyd2 is essential for regulating Na,K-ATPase activity and has diverse functions in different biological processes. The study of Fxyd2 KO mouse models has contributed to understanding its role in diseases such as neuropathic pain and has revealed beneficial metabolic adaptations related to sodium balance and glucose control, providing potential therapeutic strategies.