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

The Transforming growth factor beta (TGF-β) signaling pathway is a pleiotropic signaling cascade that regulates fundamental cellular processes such as growth, differentiation, apoptosis, and tissue homeostasis [3, 6]. Signaling is initiated when TGF-β ligands bind to a complex of type I and type II serine/threonine kinase receptors, leading to the activation of Smad transcription factors or non-canonical pathways like MAPK and PI3K [6, 12]. In the context of disease, TGF-β plays a dual role, particularly in cancer where it acts as a tumor suppressor in early stages but promotes invasion, metastasis, and immune evasion in advanced stages [2, 13]. It is also a primary driver of pathological fibrosis by stimulating the production of extracellular matrix components and inducing epithelial-mesenchymal transition [3, 15]. Therapeutic targeting of the TGF-β pathway involves several modalities, including neutralizing monoclonal antibodies, small-molecule receptor kinase inhibitors, and antisense oligonucleotides designed to inhibit ligand synthesis [1, 4, 18]. While these agents have shown promise in preclinical models, their clinical translation has been challenging due to the pathway's complex biology and significant safety risks [5, 18]. Notable adverse effects include cardiotoxicity, such as heart valve remodeling and aneurysm formation, and the development of benign or malignant skin lesions like keratoacanthomas [7, 14, 17]. Current clinical efforts are increasingly focused on combining TGF-β inhibitors with other therapies, such as immune checkpoint blockers, to overcome resistance and enhance anti-tumor immunity [2, 19, 20].

Other names

TGF-beta pathwayTGFB signalingTGF-beta signaling cascadeTransforming growth factor beta synthesis and signaling

Inhibition of TGF-β synthesis, neutralization of TGF-β ligands, inhibition of TGF-β receptor kinase activity, and blockade of latent TGF-β activation.