TABLE 3.

Novel targets under investigation for future clinical trials.

Molecules or pathway	Mechanism of action	References
Enhancing bone morphogenetic protein receptor 2 (BMPR2) signalling	Restores pSmad1/5/8 signalling and inhibits TGFβ‐induced pSmad2 expression, reducing TGFβ signalling. Blocks fibroblast differentiation and collagen production	69, 70
Epigenetic and microRNA regulation	DNA methylation inhibitors and microRNA mimics and inhibitors restore DNA methylation and microRNA levels, respectively to normal levels	71, 72
Fibulin1c inhibitors	Blocks the interaction of fibulin1c with latent TGF‐β binding protein‐1 to prevent TGF‐β activation and signalling. Blocks fibroblast differentiation and collagen production	73, 74
Immune cell regulators (e.g., checkpoint inhibitors)	Checkpoint inhibitors regulate immune/host cell interaction to regulate immune response which inhibits T cell differentiation and in turn blocks fibroblast differentiation and migration and inhibits collagen production	75, 76
Inhibitors of profibrotic macrophages	Selective depletion of profibrotic macrophages which are one of the key cells that release mediators to stimulate fibroblast differentiation and collagen production	77, 78
Modulators of cellular senescence	Senescent‐selective apoptosis (senolytic) and senescence‐associated secretory phenotype suppression (senomorphic) to induce myofibroblast apoptosis and overcome senescence in epithelial cells, respectively	79
Peroxisome proliferator‐activated receptor‐γ (PPARγ) agonists (e.g., rosiglitazone, pioglitazone)	Inhibits inflammation, smooth muscle contraction and fibrosis. Reduces TGFβ1, IL‐4, ‐5, ‐6, ‐11 and ‐13 which are profibrotic mediators	70, 80
Plasmablast and plasma cell inhibitors (e.g., bortezomib)	Targets and eliminates plasmablasts and plasma cells in the serum and tissue	81
Relaxin family peptide 1 (RXFP1) receptor agonists (e.g., CGEN25009)	Inhibits TGFβ1/Smad2 signalling and upregulates MMP‐2 and 9. Inhibits and reverses fibrosis by preventing collagen production and increasing collagen degradation	70, 82, 83, 84
STAT3 inhibitors	Block pathways regulated by IL‐6 family cytokines that are associated with fibrosis. Blocking STAT3 has wide ranging effects on immune cells, epithelial cells and fibroblasts which ultimately blocks fibroblast differentiation and collagen production	84, 85, 86

Abbreviations: BMPR2, bone morphogenetic protein receptor type 2; DNA, deoxyribonucleic acid; IL, interleukin; MMP, matrix metalloproteinase; RNA, ribonucleic acid; STAT, signal transducer and activator of transcription; TGF, transforming growth factor.