Transforming growth factor beta signaling pathway (TGF-β signaling pathway) (TGF-β signaling pathway)

The Transforming growth factor beta (TGF-β) signaling pathway is a central mediator of tissue repair and pathological fibrosis across multiple organs, including the lungs, liver, kidneys, and heart [NIH, 2022]. It is initiated by the binding of TGF-β isoforms (primarily TGF-β1) to a heterotetrameric receptor complex consisting of TGF-β type I (ALK5) and type II receptors [Frontiers, 2021]. This activation triggers the canonical SMAD pathway, where SMAD2 and SMAD3 are phosphorylated and complex with SMAD4 to regulate the transcription of profibrotic genes such as collagen, fibronectin, and alpha-smooth muscle actin (α-SMA) [Abcam, 2025]. Additionally, non-canonical pathways like MAPK, PI3K/AKT, and Rho GTPases are activated, further promoting fibroblast-to-myofibroblast transition and extracellular matrix (ECM) deposition [NIH, 2021]. In disease states, persistent activation of this pathway leads to excessive scarring and organ dysfunction [Wikipedia, 2024]. Therapeutic strategies include neutralizing antibodies, ligand traps, and small-molecule kinase inhibitors targeting ALK5, though systemic inhibition is challenged by TGF-β's pleiotropic roles in immune homeostasis and tumor suppression [MDPI, 2021].

Other names

TGF-beta signaling pathwayTGF-beta/SMAD pathwayProfibrotic TGF-beta signalingTGFB signaling

Inhibition of TGF-beta ligand binding via neutralizing antibodies or ligand traps; inhibition of TGF-beta receptor type I (ALK5) kinase activity; antisense-mediated inhibition of TGF-beta synthesis [NIH, 2021; MDPI, 2021].