Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β

The fibrotic process could be easily defined as a pathological excess of extracellular matrix deposition, leading to disruption of tissue architecture and eventually loss of function; however, this process involves a complex network of several signal transduction pathways. Virtually almost all organs could be affected by fibrosis, the most affected are the liver, lung, skin, kidney, heart, and eyes; in all of them, the transforming growth factor-beta (TGF-beta) has a central role. The canonical and non-canonical signal pathways of TGF-beta impact the fibrotic process at the cellular and molecular levels, inducing the epithelial-mesenchymal transition (EMT) and the induction of profibrotic gene expression with the consequent increase in proteins such as alpha-smooth actin (alpha-SMA), fibronectin, collagen, and other extracellular matrix proteins. Recently, it has been reported that some molecules that have not been typically associated with the fibrotic process, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), mammalian target of rapamycin (mTOR), histone deacetylases (HDAC), and sphingosine-1 phosphate (S1P); are critical in its development. In this review, we describe and discuss the role of these new players of fibrosis and the convergence with TGF-beta signaling pathways, unveiling new insights into the panorama of fibrosis that could be useful for future therapeutic targets.

Automated summary

Fibrosis is characterized by pathological excessive deposition of extracellular matrix, involving a complex network of signal transduction pathways, with TGF-β playing a central role. Additionally, molecules not typically associated with fibrosis such as NOX4, mTOR, HDAC, and S1P have been found to be critical in its development.