Slc34a2, encoding the sodium-dependent phosphate transport protein 2B (NaPi-2b), is a gene involved in the sodium-driven phosphate cotransport process. It plays a crucial role in maintaining phosphate homeostasis, especially in intestinal phosphate absorption [1]. In the context of disease, it has been associated with pathways related to cancer cell proliferation, cell cycle progression, and autophagy, as well as a rare autosomal recessive lung disease, pulmonary alveolar microlithiasis (PAM) [2-10]. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

A conditional NaPi-IIb (encoded by Slc34a2) knockout mouse demonstrated that this protein is vital for maintaining skeletal integrity during phosphate restriction. Under normal physiological conditions, the passive sodium-independent pathway may be more dominant for intestinal phosphate absorption [1]. In PAM, mutations in Slc34a2 are considered responsible. For example, a homozygous mutation c.910A > T (p.K304X) was identified in Chinese PAM patients [2]. In cancer research, loss-of-function experiments in various cancer cell lines like colorectal, esophageal, and papillary thyroid carcinoma cells have shown that Slc34a2 promotes cancer cell proliferation, cell cycle progression, and invasion through different mechanisms. For instance, in colorectal cancer, it targets TMPRSS3, and in esophageal squamous cell carcinoma, it activates STX17-mediated autophagy [3,4].

In conclusion, Slc34a2 is essential for phosphate homeostasis, especially in intestinal phosphate absorption and skeletal integrity maintenance. Its mutations are closely related to PAM, and its abnormal expression promotes cancer development in multiple types of cancers. The study of Slc34a2 using KO/CKO mouse models has significantly contributed to understanding its roles in these biological processes and disease conditions.