Ameliorating Liver Fibrosis by Highly Selective K+ Transporters-Source data

Lacking effective drugs for treating liver fibrosis accentuates the pressing need to develop reliable anti-hepatic fibrosis agents. Given the close correlation between dysregulated intracellular K+ homeostasis and the expression of transforming growth factor-beta receptor 2 (TGFβR2) which binds with TGF-β1 to activate hepatic stellate cells (HSCs) responsible for the progression of liver fibrosis, developing artificial K+ transporters capable of regulating intracellular K+ concentration offers an appealing strategy. Here, we present a novel class of ion transporters facilitating the transmembrane transport of K+ ions via a channel mechanism in a highly active and selective manner. Specifically, 6C6 exhibits an impressive EC50 value of 0.28 μM (i.e., 0.28 mol% relative to lipid) towards K+ and an exceptionally high K+/Na+ selectivity of 15.5. Unprecedentedly, the highly active and selective transport of K+ ions mediated by 6C6 results in impressive anti-hepatic fibrosis effect both in vitro and in vivo. The anti-hepatic fibrosis effect of 6C6 is achieved through a combination of multiple mechanisms, including the anti-proliferation of activated HSCs by inducing apoptosis and arresting cell cycle progression, as well as the inhibition of HSC activation by downregulating the expression of TGFβR2, which impedes the TGF-β/Smad signaling pathway.