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

Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine that serves as a master regulator of cell growth, differentiation, and immune homeostasis. In the context of indirect modulation, therapeutic strategies do not target the TGF-beta ligand or its primary receptors directly; instead, they focus on influencing the pathway's activity through secondary mechanisms. This includes inhibiting integrins like alpha-v-beta-6 that release active TGF-beta from its latent form in the extracellular matrix or using drugs like Losartan to downregulate TGF-beta expression. TGF-beta is a critical driver of fibrosis and late-stage cancer progression, where it promotes epithelial-mesenchymal transition (EMT) and creates an immunosuppressive tumor microenvironment. However, because TGF-beta also functions as a tumor suppressor in normal tissues, indirect modulation is often pursued to achieve a more localized or nuanced effect, potentially avoiding the severe systemic toxicities, such as keratoacanthomas and cardiovascular issues, associated with total pathway blockade. This approach is currently being investigated in clinical trials for conditions ranging from idiopathic pulmonary fibrosis to metastatic solid tumors.

Other names

TGFBTGF-beta pathwayTransforming growth factor beta modulationTGF-beta signaling

Indirect modulation of the TGF-beta pathway involves interfering with the activation of the latent TGF-beta complex (e.g., via integrin alpha-v-beta-6 or alpha-v-beta-8 inhibition), reducing the expression of TGF-beta ligands through upstream blockade (e.g., renin-angiotensin system inhibitors), or targeting downstream intracellular signaling mediators such as SMAD proteins.