TGF-β signaling in tissue fibrosis: Redox controls, target genes and therapeutic opportunities

► Emphasizes signaling events that regulate transcription of fibrosis-causative genes. ► ROS generation in response to TGF-β1 stimulation is rapid and precedes induction of the potent profibrotic factor plasminogen activator inhibitor-1 (PAI-1 or SERPINE1). ► Engagement of non-SMAD (e.g., EGFR, Src kinase, MAP kinases, p53) and SMAD2/3 pathways are both required for PAI-1 expression and are ROS-dependent. ► Recent findings suggest a novel role for p53 in TGF-β1-induced PAI-1 transcription that involves ROS generation and p53/SMAD interactions. ► Targeting ROS and ROS-activated cellular events is likely to have therapeutic implications in the management of fibrotic disorders, particularly in the context of prolonged TGF-β 1 signaling.