TABLE 4.
Summary of emerging therapeutic targets for IPF in drug discovery.
| Therapeutic targets | Mechanism | Ref |
|---|---|---|
| TGF-β | TGF-β is a powerful pro-fibrotic mediator | Ong et al. (2021) |
| αvβ6 Integrin | Integrin αvβ6 binds to an arginine-glycine-aspartic (RGD) sequence on LAP to activate latent form TGF-β1 | Munger et al. (1999) |
| CTGF/CNN2 | As a co-regulator of TGF-β in the pulmonary fibrosis microenvironment, CTGF can cooperate with TGF-β to participate in abnormal tissue repair processes including ECM production, fibroblast activation and differentiation | Lipson et al. (2012) |
| Galectin-3 | Modulate macrophage phenotype/Gal-3 expression and fibroblast activation, reduce the effects of key profibrotic growth factors that act on myofibroblasts, and inhibiting EMT. | Humphries et al. (2021) |
| Leukotrienes | Leukotrienes have profibrotic effects by inducing fibroblast migration, proliferation, and matrix protein synthesis | Antoniou et al. (2007) |
| ATX-LPA-LPAR | The binding of LPA-to-LPAR can promote apoptosis of epithelial cells, regulation of endothelial permeability, activation of αvβ6 integrin-mediated TGF-β signaling, secretion of IL-8, recruitment and survival of fibroblasts. ATX is the key enzyme for LPA synthesis | Tager et al. (2008); Ninou et al. (2018); Suryadevara et al. (2020) |
| SPHK1-S1P-S1PR | The binding of S1P-to-S1PR can lead to mitochondrial reactive oxygen species (mtROS) and promote YAP1 to enter cell nuclei, affecting the differentiation of myofibroblasts and matrix remodeling. SPHK1 is the key enzyme for S1P synthesis | Huang et al. (2020) |
| PTX-2/SAP | As a ligand for the Fcγ receptor, PTX-2 downregulates monocyte and macrophage activity (especially M2) | Castaño et al. (2009) |
| JAK | JAK/STAT is a downstream pathway of IL-6, IL-11, IL-13, PDGF, TGF-β1 and FGF. The effect of JAK/STAT phosphorylation on cellular fibrotic processes includes proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition | Montero et al. (2021) |
| Src | Src is a group of nonreceptor tyrosine kinases, which participate in the TGF-β pathway by activating FAK. | Hu et al. (2014) |
| PI3K/Akt/mTOR | PI3K/Akt/mTOR plays a critical role in cell survival, growth, proliferation, protein synthesis, and EMT. In vitro, mTOR inhibitors can reduce TGF-β-induced fibroblast proliferation and type I collagen synthesis | Hennessy et al. (2005); Mercer et al. (2016); Lawrence and Nho, (2018) |
| Smo receptor | Smo is an important mediator of hedgehog signaling which is reactivated in adulthood within IPF | Effendi and Nagano, (2021) |
| Nitric oxide synthase | Activated macrophages, contributing to the cellular injury mediated by ROS, produce both nitric oxide (NO) and peroxynitrite | Giri, (2003) |
| GPR40/GPR84 | GPR40 and GPR84 are G protein coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. PR40 agonist and GPR84 antagonists act on cells that involved in fibrotic pathways: macrophages, fibroblasts, and epithelial cells, and finally reduce inflammation | Gagnon et al. (2018) |
| LOX and LOXL | Lysyl oxidase (LOX) and LOX-like (LOXL) are enzymes involved in collagen cross-linking | Chen et al. (2019) |