Enpp1, also known as ectonucleotide pyrophosphatase/phosphodiesterase 1, codes for a type 2 transmembrane glycoprotein. It primarily functions in regulating skeletal and soft tissue mineralization by generating pyrophosphate, a key inhibitor of hydroxyapatite formation. It is also involved in purinergic signaling pathways through hydrolyzing extracellular ATP [1,3].

In breast cancer, Enpp1 loss-of-function in both cancer and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing its cGAMP hydrolysis activity phenocopied Enpp1 knockout in a STING-dependent manner, indicating that restoring paracrine cGAMP-STING signaling is a dominant anti-cancer mechanism of Enpp1 inhibition [2]. In HER2+ breast cancer, genetic ablation of Enpp1 from brain metastatic cells prevented endothelial cell dysfunction, reduced metastatic burden, and prolonged survival, suggesting its role in blood-brain barrier dysfunction and brain metastasis formation [4]. In addition, in a model of radiation enteritis, T cell-derived apoptotic extracellular vesicles with surface Enpp1 alleviated the condition by hydrolyzing extracellular and intracellular cGAMP and inhibiting the cGAS-STING pathway [5].

In conclusion, Enpp1 is crucial for regulating mineralization and is involved in multiple disease processes. Gene knockout and conditional knockout mouse models have been instrumental in revealing its role in cancer metastasis, blood-brain barrier function, and radiation-induced inflammation, providing valuable insights into potential therapeutic strategies for these diseases.