Snx3, or sorting nexin 3, is a retromer-associated cargo binding protein involved in multiple cellular processes. It participates in endosomal sorting, which is crucial for various cellular functions such as receptor recycling and protein trafficking. The protein is involved in pathways like Wnt/β-catenin signaling, which is associated with carcinogenesis and metastasis, and also has a role in maintaining iron homeostasis [2,3,4,5].

In mouse models, cardiomyocyte-specific Snx3 knockout (SNX3Cko) normalized heart contractile/relaxation function and alleviated doxorubicin-induced myocardial injury by regulating GPX4-mediated ferroptosis [1]. Cardiac-specific Snx3 knockout (Snx3-cKO) also significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis, while Snx3 transgenic (Snx3-cTg) mice were more susceptible to Dox-induced ferroptosis and cardiomyopathy. Mechanistically, SNX3 facilitated the recycling of transferrin 1 receptor (TFRC), disrupting iron homeostasis [2]. Snx3-/-mutant mouse embryos showed a fully-penetrant cranial neural tube defect (NTD), with decreased canonical WNT target gene expression and a defect in convergent extension of the neural epithelium. Rescue of NT closure in Snx3-/-embryos with a WNT agonist demonstrated the importance of SNX3 in WNT signaling regulation [3].

In conclusion, Snx3 is essential for endosomal sorting, Wnt signaling regulation, and iron homeostasis. Studies using Snx3 KO/CKO mouse models have revealed its role in doxorubicin-induced cardiomyopathy and neural tube closure, providing potential therapeutic targets for related diseases.