The pivotal role of TGF-β/Smad pathway in fibrosis pathogenesis and treatment.

Fibrosis, which is characterized by pathological extracellular matrix (ECM) accumulation impairing organ function, is governed primarily by dysregulated transforming growth factor-β (TGF-β)/Smad signalling. TGF-β1 triggers canonical (Smad2/3-dependent) and noncanonical pathways upon receptor binding, driving profibrotic processes such as fibroblast activation, epithelial-mesenchymal transition (EMT), excessive ECM production (e.g., collagen), and the suppression of matrix degradation. This pathway is central to organ-specific fibrogenesis: In liver fibrosis, it activates hepatic stellate cells (HSCs); in renal fibrosis, it promotes tubular injury and ECM deposition; in pulmonary fibrosis, it induces EMT/fibroblast transition in radiation/bleomycin models; in cardiac fibrosis, it mediates fibroblast activation in diabetic cardiomyopathy/atrial fibrillation via NPRC/TGIF1/USP mechanisms; and in skin fibrosis (e.g., scleroderma), it stimulates collagen overproduction, which is suppressed by osthole or mesenchymal stem cells. The TGF-β/Smad axis thus represents a pivotal therapeutic target. Future research should clarify tissue-specific regulatory networks and develop combinatorial antifibrotic strategies.