TGF-β1 signaling in Crohn’s disease

Crohn's disease (CD), a chronic inflammatory disorder of the gastrointestinal tract, arises from the intricate interplay among genetic predisposition, environmental triggers, and gut microbial communities. Transforming growth factor β1 (TGF-β1) signaling plays crucial roles in modulating intestinal microbiota, immune responses, tissue fibrosis, and colitis-associated cancer (CAC) development in CD patients. TGF-β1 functions as a key immune regulator by modulating T-cell differentiation, particularly influencing Th17 and regulatory T (T reg ) cells, which are central to the inflammatory processes in CD. Smad7 overexpression has been reported in the inflamed mucosa of active CD patients, where it may disrupt TGF-β1 signaling and impair immune tolerance, thereby contributing to persistent inflammation, dysbiosis, and a compromised intestinal barrier. Further, TGF-β1 promotes fibrosis through multiple mechanisms, including canonical (Smad-dependent) and non-canonical (non-Smad) signaling pathways, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition, and downstream cytokines associated microenvironment. However, the dual role of TGF-β1 in CAC remains unclear. Although it appears to suppress tumor development in the early stages, it may contribute to cancer progression in later stages. To clarify the multifaceted roles of TGF-β1 across the CD continuum, this review summarizes the latest understanding of TGF-β1 signaling in CD, including its roles in immune modulation, microbiota interaction, fibrosis, and CAC progression, as well as potential therapeutic approaches targeting these pathways.