Smad3 is a key mediator of TGF-β signaling. It can be activated by TGF-β1 and other stress molecules like angiotensin II, AGEs, and CRP under disease conditions. It also interacts with pathways such as ERK/p38 MAPK and NF-κB, playing a crucial role in many biological processes including inflammation and fibrosis [1].

Smad3 null mice have shown resistance to various fibrotic conditions. For instance, they are resistant to radiation-induced cutaneous fibrosis, bleomycin-induced pulmonary fibrosis, carbon tetrachloride-induced hepatic fibrosis, glomerular fibrosis induced by streptozotocin-induced type 1 diabetes, and fibrotic responses in conditions like proliferative vitreoretinopathy, ocular capsule injury, and glomerulosclerosis from unilateral ureteral obstruction [2]. This indicates that Smad3 is a major contributor to the pro-fibrotic activities of TGF-β.

In conclusion, Smad3 is essential in TGF-β-mediated biological processes, especially in fibrosis. Studies using Smad3 knockout mouse models have clearly demonstrated its role in multiple fibrotic disease conditions, highlighting its potential as a therapeutic target for treating pathological fibrotic diseases [2].