Smad3 is a key mediator of the TGF-β signaling pathway. It plays a crucial role in multiple biological processes such as cell proliferation, differentiation, tissue repair, and fibrosis [1,2,3,4]. It can interact with other signaling pathways like ERK/p38 MAPK and NF-κB, and is also involved in regulating many downstream target genes including non-coding RNAs [1].

Smad3-null mice have been used to study its functions. These mice are resistant to various types of fibrosis, including radiation-induced cutaneous fibrosis, bleomycin-induced pulmonary fibrosis, carbon tetrachloride-induced hepatic fibrosis, and glomerular fibrosis induced by type 1 diabetes [3]. In fibrotic conditions resulting from epithelial-to-mesenchymal transdifferentiation (EMT), such as proliferative vitreoretinopathy, ocular capsule injury, and glomerulosclerosis from unilateral ureteral obstruction, Smad3-null mice show an abrogated fibrotic response [3].

In conclusion, Smad3 is essential in the TGF-β signaling pathway and significantly contributes to fibrosis in multiple organs. The use of Smad3-null mouse models has provided valuable insights into its role in fibrotic diseases, highlighting its potential as a therapeutic target for treating pathological fibrotic conditions [3].

References:

1. Wu, Wenjing, Wang, Xiaoqin, Yu, Xueqing, Lan, Hui-Yao. 2022. Smad3 Signatures in Renal Inflammation and Fibrosis. In International journal of biological sciences, 18, 2795-2806. doi:10.7150/ijbs.71595. https://pubmed.ncbi.nlm.nih.gov/35541902/

2. Yamaguchi, Takashi, Yoshida, Katsunori, Murata, Miki, Matsuzaki, Koichi, Naganuma, Makoto. 2022. Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis. In International journal of molecular sciences, 23, . doi:10.3390/ijms23116270. https://pubmed.ncbi.nlm.nih.gov/35682957/

3. Flanders, Kathleen C. . Smad3 as a mediator of the fibrotic response. In International journal of experimental pathology, 85, 47-64. doi:. https://pubmed.ncbi.nlm.nih.gov/15154911/

4. Gao, Zhen. 2025. New insights into Smad3 in cardiac fibrosis. In Gene, 952, 149418. doi:10.1016/j.gene.2025.149418. https://pubmed.ncbi.nlm.nih.gov/40089084/