Ampd3, also known as adenosine monophosphate deaminase 3, is an isoenzyme involved in the regulation of the energetic metabolism of mammalian cells, catalyzing the conversion of AMP to IMP [3,5]. It plays a crucial role in nucleotide metabolism and energy charge, and is especially important in erythrocytes where it is the key catabolic enzyme for 5'-AMP [7]. Genetic models, such as gene knockout (KO) mice, have been instrumental in studying its functions.

In a mouse model of chronic kidney disease (CKD), genetic ablation of Ampd3 in erythrocytes preserves the adenine nucleotide pool, activates the AMPK-BPGM axis, enhances O₂ delivery and antioxidative stress capacity, protecting against renal hypoxia, damage, and CKD progression. This shows that Ampd3 is part of an erythrocyte purinergic hypoxia-sensing and energy-regulating axis [1]. In DOX-induced cardiotoxicity, Ampd3 knockout mice have improved ejection fractions and reduced myocardial injury. Transcriptome sequencing reveals reduced levels of related proteins, and it is shown that Ampd3 interacts with HSP90α, activating DRP1 and leading to mitochondrial fission, ROS release, and ferroptosis [2]. In gastrointestinal stromal tumors (GISTs), depletion of Ampd3 in GIST-T1 cells using siRNA suppresses cell migration and invasion, and sensitizes cells to the tyrosine kinase inhibitor imatinib, indicating its association with the malignant characteristics of GISTs [4]. In anthrax LeTx-induced macrophage cell death, Ampd3 deficiency impairs an unknown downstream event linked to cell death, despite not affecting LeTx entry or MKK cleavage [5]. In autosomal dominant polycystic kidney disease (ADPKD) mouse models, inhibition of Ampd3, a SE-driven and CDK7-controlled metabolic target gene, delays cyst growth [6].

In conclusion, Ampd3 plays diverse and essential roles in various biological processes and disease conditions. KO mouse models have been vital in revealing its role in CKD, cardiomyopathy, GISTs, macrophage cell death, and ADPKD. These studies provide insights into the underlying mechanisms and potential therapeutic targets for these diseases.