Smad7, a member of the I-Smads family, is a key negative regulator of the TGF-β signaling pathway [5,7]. TGF-β is a pleiotropic cytokine involved in diverse cellular processes such as cell growth, differentiation, and immune regulation. Smad7 antagonizes TGF-β signaling through multiple mechanisms in the cytoplasm and nucleus, and it can also serve as a cross-talk mediator between the TGF-β signaling pathway and other pathways. It plays pivotal roles in embryonic development, adult homeostasis, and is associated with various human diseases including cancer, tissue fibrosis, and inflammatory diseases [7].

In the context of solid tumors, co-expressing SMAD7 with a HER2-targeted CAR in engineered T cells enhanced their cytolytic efficacy, resistance to TGF-β-triggered exhaustion, and reduced inflammatory cytokine production. This led to persistent tumor growth inhibition and improved survival in tumor-challenged mice [1]. In hypertrophic scar formation, HDAC5-mediated Smad7 silencing through MEF2A was critical for fibroblast activation. Depletion of HDAC5 increased Smad7 expression, attenuated HS formation, and inhibited fibroblast activation [2]. In bladder cancer, nuclear circNCOR1 epigenetically promoted SMAD7 transcription, inhibiting the TGFβ-SMAD signaling pathway and lymph node metastasis [3]. In immune-mediated disorders, Smad7, an inhibitor of TGF-β1 signaling, was involved in diseases like psoriasis, rheumatoid arthritis, MS, and inflammatory bowel diseases. Clinical trials with mongersen, a Smad7 antisense oligonucleotide, in Crohn's disease patients had discordant results [4]. In inflammatory bowel diseases, high levels of Smad7 led to defective TGF-β1/Smad signaling. Pharmacological inhibition of Smad7 restored TGF-β1 function and reduced inflammation [6,8]. In chronic kidney diseases, gene transfer of Smad7 inhibited renal fibrosis and inflammation by blocking Smad2/3 activation and the NF-κB-dependent inflammatory pathway [9].

In conclusion, Smad7 is a crucial regulator of the TGF-β signaling pathway. Its role has been elucidated through various in vivo studies, especially in models related to solid tumors, hypertrophic scar formation, bladder cancer, immune-mediated disorders, inflammatory bowel diseases, and chronic kidney diseases. These model-based studies have shown that Smad7 can either promote or inhibit disease-related processes, highlighting its potential as a therapeutic target in these disease areas.