SMAD7: riding on fibrosis-limiting routes and beyond

Fibrosis, marked by excessive extracellular matrix deposition, underlies the progression of major organ pathologies, including cardiac and skeletal muscle diseases. Central to fibrotic remodeling is the persistent activation of myofibroblasts, orchestrated by profibrotic mediators such as transforming growth factor-beta (TGF-β). SMAD7, a key inhibitor of TGF-β signaling, has emerged as both an antifibrotic effector and a modulator of immune and tissue remodeling responses. New insights reveal that SMAD7 exerts cell-specific antifibrotic effects, particularly within myofibroblasts, limiting macrophage-driven fibrogenesis through paracrine mechanisms. Moreover, the integration of SMAD7 modulation into engineered cellular therapies, such as CAR-T cells, highlights its potential to enhance regenerative outcomes and immune resilience against fibrosis. Here, we review the expanding role of SMAD7 in cardiac, skeletal muscle, and vascular tissues, emphasizing its promise as a therapeutic target for reprogramming fibrosis, promoting tissue repair, and restoring organ function in chronic disease settings.