MerTK inhibition for the treatment of organ fibrosis

Abstract

Background: The evolution of multi-chronic diseases is largely influenced by fibrosis, which acts as a key route. However, effective and low side-effect antifibrotic therapies remains limited. In organ fibrosis, scarring mainly driven by transforming growth factor-β (TGF-β) is a pivotal contributor to disease progression. However, ubiquitously expressed TGF-β is hard to be applied in fibrosis therapy, and identification of refined alternative targets to inhibit TGF-β signalling is needed.In recent studies, researchers have uncovered new genetic risk variants of myeloid-epithelial reproductive tyrosine kinase (MerTK). Previous studies have shown a significant correlation between these polymorphisms and liver fibrosis progress. This study investigates the potential of MerTK as a new therapeutic target for multiorgan fibrosis, including liver, kidney, and lung, as well as the underlying processes involved in its therapeutic activities.Methods: MerTK and TGF-β interaction was investigated in vitro. Fibrosis models of liver (bile duct ligation), kidney (unilateral ureteral obstruction) and lung (bleomycin injection) were established by Mertk knockout mice to explore their role in the fibrosis process of each organ. The mechanism of MerTK was explored through RNA-seq, ATAC-seq and Cut&Tag-seq.Results: I identified MerTK as a TGF-β-inducible nodal effector of organ fibrosis that is upregulated in multiple fibrotic organs in mice. TGF-β elicits a rapid upregulation of MerTK expression in fibroblast. MerTK, on the other hand, can stimulate further production of TGF-β and facilitate the activation of profibrotic TGF-β/SMAD and non-SMAD signaling pathways. Conclusion: The findings combining in vitro, and in vivo investigations have provided evidence that MerTK functions as a novel regulator of fibrosis across several organs by involving shared core pathway. This research proposes that MerTK may serve as a promising therapeutic target for the treatment of multiorgan fibrosis.