Smad3 is a key mediator of the transforming growth factor-β (TGF-β) signaling pathway [1,3,4,5,6]. It plays a crucial role in various biological processes such as cell proliferation, differentiation, tissue repair, and fibrosis [6]. By interacting with other signaling pathways like ERK/p38 MAPK and NF-κB, Smad3 also mediates inflammation [1]. Genetic models, especially knockout (KO) mouse models, have been instrumental in studying its functions.

In KO mouse models, Smad3 null mice are resistant to various types of fibrosis. For example, they are resistant to radiation-induced cutaneous fibrosis, bleomycin-induced pulmonary fibrosis, carbon tetrachloride-induced hepatic fibrosis, and glomerular fibrosis induced by streptozotocin-induced type 1 diabetes [4]. In fibrotic conditions resulting from epithelial-to-mesenchymal transdifferentiation (EMT) like proliferative vitreoretinopathy, ocular capsule injury, and glomerulosclerosis from unilateral ureteral obstruction, Smad3 null mice show an abrogated fibrotic response [4]. In the context of non-alcoholic steatohepatitis (NASH), different phosphorylated isoforms of Smad3 have distinct roles in hepatic carcinogenesis [3]. In cancer, EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis [2].

In summary, Smad3 is essential in TGF-β signaling, regulating multiple biological processes. The use of Smad3 KO mouse models has significantly advanced our understanding of its role in fibrosis-related diseases, as well as in cancer metastasis and NASH-associated hepatic carcinogenesis [2,3,4].

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. Huang, Changsheng, Hu, Fuqing, Song, Da, Hu, Junbo, Wang, Guihua. . EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis. In The Journal of clinical investigation, 132, . doi:10.1172/JCI152394. https://pubmed.ncbi.nlm.nih.gov/35085106/

3. 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/

4. 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/

5. Gu, Yue-Yu, Liu, Xu-Sheng, Lan, Hui-Yao. 2023. Therapeutic potential for renal fibrosis by targeting Smad3-dependent noncoding RNAs. In Molecular therapy : the journal of the American Society of Gene Therapy, 32, 313-324. doi:10.1016/j.ymthe.2023.12.009. https://pubmed.ncbi.nlm.nih.gov/38093516/

6. 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/