Smad5, short for small mothers against decapentaplegic 5, is a receptor-regulated member of the Smad family proteins. It mainly functions in its phosphorylated form within the bone morphogenetic protein (BMP) signaling pathway. Smad5 is involved in numerous biological processes such as proliferation, differentiation, apoptosis, anti-fibrosis, and mitochondrial function metabolism, thus holding great biological importance. Genetic models, like KO/CKO mouse models, are valuable tools for studying its functions [1].

In mouse models, deletion of SMAD1/5 using progesterone receptor (PR)-cre led to endometrial defects, including cystic endometrial glands, hyperproliferative endometrial epithelium during the implantation window, and impaired apicobasal transformation, resulting in infertility, indicating its crucial role in endometrial receptivity and embryo implantation [2]. In pulmonary arterial hypertension (PAH) functional studies, two SMAD5 variants in pulmonary artery smooth muscle cells (PASMCs) showed different effects on cell viability, with one promoting proliferation and the other increasing apoptosis, suggesting SMAD5 as a potential novel PAH gene [3].

In conclusion, Smad5 has diverse essential biological functions mainly through the BMP signaling pathway. Studies using KO/CKO mouse models have revealed its significance in endometrial receptivity and implantation, as well as its potential role in PAH, enhancing our understanding of related biological processes and disease mechanisms.