Exploring Smad5: a review to pave the way for a deeper understanding of the pathobiology of common respiratory diseases.

Smad5 (small mothers against decapentaplegic 5) protein is a receptor-regulated member of the Smad family proteins, mainly participating in the bone morphogenetic protein (BMP) signaling pathway in its phosphorylated form. This article will provide a detailed review of Smad5, focusing on its gene characteristics, protein structure, and subcellular localization properties. We will also explore the related signaling pathways and the mechanisms of Smad5 in respiratory diseases, including chronic obstructive pulmonary disease (COPD), bronchial asthma, pulmonary arterial hypertension(PAH), lung cancer, and idiopathic pulmonary fibrosis (IPF). Additionally, the review will cover aspects such as proliferation, differentiation, apoptosis, anti-fibrosis, and mitochondrial function metabolism. In addition, the review will cover aspects of proliferation, differentiation, apoptosis, anti-fibrosis and functional mitochondrial metabolism related to the above topics. Numerous studies suggest that Smad5 may play a unique and important role in the pathogenesis of respiratory system diseases. However, in previous research, Smad5 was mainly used to broadly determine the activation of the BMP signaling pathway, and its own function has not been given much attention. It is worth noting that Smad5 has distinct nuclear-cytoplasmic distribution characteristics different from Smad1 and Smad8. It can undergo significant nuclear-cytoplasmic shuttling when intracellular pH (pHi) changes, playing important roles in both the classical BMP signaling pathway and non-BMP signaling pathways. Given that Smad5 can move intracellularly in response to changes in physicochemical properties, its cellular localization may play a crucial role in the development of respiratory diseases. This article will explore the possibility that its distribution characteristics may be an important factor that is easily overlooked and not adequately considered in disease research.