Smad2, a member of the SMAD family, is a key intracellular mediator in the signaling pathways of the Transforming Growth Factor-β (TGF-β) superfamily. It plays a crucial role in conveying signals from cell-surface serine/threonine kinase receptors to the nucleus, where it controls gene expression. This process is essential for various biological processes such as cell differentiation, development, and tissue homeostasis [2].

In liver-related research, exposure to polystyrene microplastics can cause liver fibrotic injury in mice. This occurs through the activation of the ROS/TGF-β/Smad2/3 signaling axis, which leads to macrophage extracellular traps formation and subsequent hepatocellular inflammatory response and epithelial-mesenchymal transition [1]. In melanoma, the NEAT1/miR-200b-3p/SMAD2 axis promotes melanoma progression by activating the EMT signaling pathway and immune responses [3]. In rheumatoid arthritis, SMAD2 inhibits the pyroptosis of fibroblast-like synoviocytes and the secretion of inflammatory factors via the TGF-β pathway [4]. Also, coffee consumption may slow fibrogenesis in chronic liver disease patients, possibly due to caffeine-induced degradation of Smad2, impairing TGF-β signaling [5]. In ovarian cancer, TMED3 stabilizes SMAD2 by counteracting NEDD4-mediated ubiquitination, promoting cancer progression [6].

In conclusion, Smad2 is a vital component in the TGF-β signaling pathway, significantly influencing multiple biological processes and disease conditions. Research using various models, though not specifically KO/CKO mouse models in the provided references, has revealed its role in liver fibrotic injury, melanoma progression, rheumatoid arthritis, chronic liver disease, and ovarian cancer. Understanding Smad2's functions offers potential insights into disease mechanisms and therapeutic targets for these conditions.