Smad5, also known as 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, acting as an intracellular signal transducer for the transforming growth factor-beta superfamily [1,2]. It is crucial for various biological processes such as embryonic development, hematopoiesis, osteogenesis, and adult homeostasis [2,5]. Genetic models, especially KO/CKO mouse models, have been valuable for studying its functions.

In mouse models, female mice with SMAD1/5 deletion display endometrial defects, including cystic endometrial glands, hyperproliferative endometrial epithelium during the implantation window, and impaired apicobasal transformation, leading to infertility, indicating its importance in endometrial receptivity and embryo implantation through the ACVR2A-SMAD1/SMAD5 axis [3]. In pulmonary arterial hypertension (PAH) functional studies, two SMAD5 variants identified in patients led to significant changes in cell viability and apoptosis in pulmonary artery smooth muscle cells (PASMCs), suggesting SMAD5 as a potential novel PAH gene [4]. Also, circ-Smad5 retards the proliferation and cell cycle progression of JB6 cells by inhibiting the activation of the Wnt/β-catenin/Lef 1 signaling pathway [6].

In conclusion, Smad5 plays essential roles in multiple biological processes, especially in endometrial receptivity, hematopoiesis, osteogenesis, and cell cycle regulation. The study of Smad5 using KO/CKO mouse models and other functional studies has provided insights into its functions in diseases like PAH, highlighting its significance in understanding disease mechanisms and potentially developing new therapeutic strategies.