Cnnm4, or Cyclin and CBS domain divalent metal cation transport mediator 4, is a key magnesium (Mg²⁺) transporter. It plays a crucial role in Mg²⁺ homeostasis, which is essential for energy metabolism, muscle contraction, and neurotransmission. Mg²⁺, as part of the Mg-ATP complex, is involved in over 600 enzymatic reactions [2]. In the body, Cnnm4 facilitates the transcellular absorption of Mg²⁺ in the colon [2]. It is also associated with pathways related to cell proliferation, differentiation, and thermogenesis, and its function is important for maintaining the dynamic homeostasis of epithelial tissues [3,4]. Genetic models, such as gene knockout mouse models, can be used to study Cnnm4's function.

In Cnnm4-deficient mice, cell proliferation is promoted and cell differentiation is partly suppressed in the colon epithelia, making them more vulnerable to cancer development. Ca²⁺ influx stimulated by capsaicin is impaired, and EGF receptor signaling is constitutively activated. Administration of an EGF receptor inhibitor cancels the augmented cell proliferation [4]. In ApcΔ(14/+) mice, deletion of Cnnm4 promotes the malignant progression of intestinal polyps to adenocarcinomas, and in human colon cancer tissues, CNNM4 expression is inversely related to malignancy, indicating that CNNM4-dependent Mg²⁺ efflux suppresses tumor progression by regulating energy metabolism [6].

In conclusion, Cnnm4 is essential for Mg²⁺ homeostasis and plays a significant role in maintaining the dynamic balance of epithelial tissues, especially in the colon. The study of Cnnm4 knockout mouse models has revealed its importance in tumor progression, highlighting its potential as a therapeutic target for cancer treatment. Additionally, its role in Jalili syndrome, a disorder causing cone-rod dystrophy and amelogenesis imperfecta, shows its significance in visual and dental development [1,5,7].